Substituted benzamides and their uses

ABSTRACT

Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication No. 61/623,517 filed on Apr. 12, 2012, and from U.S.Provisional Patent Application No. 61/791,823 filed on Mar. 15, 2013,which are hereby incorporated by reference in their entirety, and is anational stage application of PCT application PCT/US2013/036229, havingan international filing date of 11 Apr. 2013, the disclosure of which isincorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENTAL SUPPORT

This invention was made with Government support under contract CA 082566awarded by the National Institutes of Health. The Government has certainrights in this invention.

FIELD OF THE INVENTION

The present invention relates to novel GLUT1 inhibitors and modulatorcompounds useful for the treatment of various diseases. Moreparticularly, the invention is concerned with such compounds, methods ortreating diseases and methods of synthesis of the compounds.

BACKGROUND OF THE INVENTION

The concept of synthetic lethality, or conditional genetics, describesthe genetic interaction of two genes, both involved in a cellularprocess. When either gene is mutated alone, the cell remains viable.However, the combination of mutations in these two genes results in celldeath (Hartwell, et al., Science, 278:1064-1068 (1997)). In the case ofchemical synthetic lethality, the first mutation is essential to thedevelopment of cancer, while a second gene is inhibited by a smallmolecule, resulting in cytotoxic cell death (Kaelin, W. G., Jr., Nat RevCancer, 5:689-698 (2005); Sutphin, et al., Cancer Res., 67:5896-5905(2007)). This approach is particularly attractive because it should notaffect normal, non-cancerous tissue. Furthermore, synthetic lethality isa therapeutically advantageous approach to drug discovery and isparticularly suited to developing therapeutics to treat cancers. Itdescribes a genetic interaction whereby the combination of mutationand/or inhibition of two genes leads to tumor cell death. If only one ofthese two genes is altered, there are no deleterious effects. Forexample, in the vast majority of renal carcinomas, the VHL tumorsuppressor gene is inactivated, driving growth and expansion.

Conventional chemotherapeutic agents have been identified only by theirability to kill rapidly proliferating cells and therefore such agentscannot distinguish between normal, healthy dividing cells and tumorcells. For this reason, standard agents have low therapeutic indices andare often limited by their severe toxicity to normal tissue. While manysolid tumors respond to different combinations of cytotoxicchemotherapies, kidney cancer is a particularly intractable disease.Renal cell carcinoma (RCC), the most common type of kidney cancer, hasproven to be particularly challenging, resistant to both radiationtherapy and standard systemic chemotherapies (Atkins, et al., ClinCancer Res., 10:6277 S-6281 S. (2004); Motzer, R. J., and Russo, P., JUrol., 163:408-417 (2000)). To date, immunotherapy using interferon orinterleukin-2 has had mild success with responses in less than 10% ofpatients with metastatic RCC (Rosenberg, et al., Ann Surg., 228:307-319(1998)). The recent development of anti-angiogenic therapies sunitinib(Sutent) and sorafenib (Nexavar) is encouraging although these agentsare not curative (Ahmad, T., and Eisen, T., Clin Cancer Res., 10:6388S-6392S (2004); Motzer, et al., J Clin Oncol., 24:16-24 (2006)). Thetargeting of receptor tyrosine kinases, which is not specific to thedevelopment of RCC, has become the standard of care for advanced RCC(Rathmell, et al., Curr Opin Oncol., 19:234-240 (2007)). One keydistinguishing feature in RCC is the loss of function of the VHL tumorsuppressor gene, an essential and frequent mutation in the developmentof RCC. In order to specifically target RCC cells without toxicity tonormal cells, we have employed a synthetic lethal approach, seeking toidentify compounds that exhibit selective cytotoxicity to cells thathave lost functional VHL.

Tumor hypoxia has a well defined role in driving tumor progression andmetastasis, as well as resistance to therapy. A key mediator of hypoxicstress is HIFα. HIF is a bHLH heterodimeric transcription factor, madeup of an oxygen-labile subunit (HIF-α) and a constitutive subunit(HIF-β). In the presence of oxygen, hydroxylation on proline residues564 and 402 by prolyl hydroxylases (PHDs) marks HIF-α for recognitionand binding with Von Hippel-Lindau protein (pVHL), leading todegradation of HIF-α. Under hypoxic conditions, activity of the PHDsdecrease, which prevents the recognition of HIF-α by pVHL. In cells thatlack VHL, stabilized HIF-α binds HIF-β to activate the transcription ofgenes involved in several processes. HIF transcribes genes that mediateglycolysis, angiogenesis, tissue remodelling, epithelial permeabilityand vascular tone. These genes, and processes driven by these genes, actto promote tumor growth and survival in hypoxic conditions.

Functional studies indicate that pVHL, the protein product of VHL, is anE3 ubiquitin ligase that targets the α-subunit of the hypoxia-induciblefactor (HIF) for proteasomal degradation under normoxia. In addition toits role in HIF regulation, pVHL has been implicated in a variety ofprocesses including extracellular matrix assembly, regulation ofmicrotubule stability, polyubiquitination of atypical PKC familymembers, regulation of fibronectin, and RNA polymerase II subunits.Glucose transporter 1 (GLUT1), also known as solute carrier family 2(SLCA2) or facilitated glucose transporter member 1 (SLC2A1) is a 492amino acid protein (NCBI accession numbers NP_(—)006507.2 or P11166.2).GLUT1 is a member of a small family 45-55 kDa hexose transport proteinsand is invovled in facilitating the transport of glucose across theplasma membranes of mammalian cells. (See, e.g., Doege et al., BiochemJ., 15:(359):443-449 (2001); Mueckler, et al., Science 229(4717):941-945(1985); and Olsen et al., Annual Review of Nutrition, 16:235-256(1996)).

There is considerable interest in the identification of inhibitors ofHIF and its downstream genes such as GLUT1. A variety of pharmacologicalHIF inhibitors have been identified, although the interaction of theseagents is not directly with HIF, but via modulation of cellularprocesses in which HIF is integral.

An extension of this therapy would be in the treatment of cellsdefective in the von Hippel-Lindau gene and diseases associated withsuch defects or inhibition of downstream pathways such as inhibition ofGLUT1 activity.

Identifying new molecular targeted therapies that specifically killtumor cells while sparing normal tissue is the next major challenge ofcancer research. A characteristic of VHL-deficient cells, namelyreliance on GLUT1 and aerobic glycolysis can now be exploited intreatment of diseases related to rapidly dividing cells. High-throughputchemical synthetic lethal screens have been used to identifiy smallmolecules that exploit the loss of the von Hippel-Lindau (VHL) tumorsuppressor gene, which occurs in approximately 80% of renal carcinomas.These small molecules selectively kill cells with mutant VHL but notcells with wild-type VHL by specifically targeting glucose uptake viaGLUT1 in VHL-deficient tumors, which are dependent on glycolysis for ATPproduction. The present application describes small molecules thatimpair glucose transport in VHL-deficient cells, but not in cells withwild-type VHL, resulting in specific killing of renal carcinoma cells.The potential to target glucose uptake in VHL-deficient tumorstherapeutically with the use of small molecules provides a new way totreat metastatic renal carcinoma, among others types of diseasesmediated by elevated expression of GLUT1. Treatment with these smallmolecules inhibits the growth of VHL-deficient tumors by binding GLUT1directly and impeding glucose uptake in vivo without toxicity to normaltissue.

SUMMARY OF THE INVENTION

Provided herein are compounds of Formula I:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers and stereoisomers thereof;wherein

-   -   A is a nitrogen-containing heteroaryl ring chosen from        pyridinyl, pyrazinyl, and imidazolyl, each of which is        optionally substituted;    -   X is CH₂CH₂NR, CH₂NR, or NR wherein each R is independently        chosen from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocycloalkyl, and heteroaryl, each of which, except for        hydrogen, is optionally substituted;    -   R₁, R₂, R₃, R₄, R₅, and R₆ are each independently chosen from        hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocycloalkyl, and heteroaryl, each of which, except for        hydrogen, is optionally substituted;    -   Y is chosen from O, S, NR; wherein each R is independently        chosen from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocycloalkyl, and heteroaryl, each of which, except for        hydrogen, is optionally substituted;    -   B is an optionally substituted aryl ring;    -   provided that if A is 3-pyridinyl, X is CH₂NH, R₁, R₂, and R₄        are each hydrogen, R₃ is Me, and Y is O, then B is not phenyl or        4-methylphenyl.

In one aspect, compounds of Formula II are provided:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein:

-   -   C is a nitrogen-containing heteroaryl ring chosen from        pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, pyrazolyl,        imidazolyl, and thiazolyl, each of which is optionally        substituted;

is attached to the phenyl ring at either the 3 or 4 position;

-   -   R₇, R₈, and R₉ are each independently chosen from hydrogen,        optionally substituted alkyl, and optionally substituted        alkenyl;    -   R₁₀ is chosen from hydrogen, hydroxy, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkoxy, optionally substituted cycloalkyl, optionally        substituted aryl, optionally substituted heterocycloalkyl,        optionally substituted heteroaryl, halo, carboxy, nitro,        sulfonyl, sulfinyl, and optionally substituted amino;    -   W is chosen from —NRSO₂—, —SO₂NR—, and —NRCO—, wherein each R is        independently chosen from hydrogen, alkyl, alkenyl, alkynyl,        cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of        which, except for hydrogen, is optionally substituted; and    -   D is heteroaryl.

In one embodiment, the compounds of Formula II are of the Formula IIA:

wherein

-   -   X₁ and X₂ are each independently chosen from N, NO, and CH,        provided that at least one of X₁ and X₂ is not CH;    -   each D is individually taken from the group consisting of C, CH,        NH, N, S and O, such that the resultant ring is selected from        pyridyl, furanyl, imidazolyl, triazolyl, and thienyl;    -   R₇, R₈, and R₉ are each independently chosen from hydrogen,        optionally substituted alkyl, and optionally substituted        alkenyl;    -   R₁₀ and R₁₁ are independently chosen from hydrogen, hydroxy,        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkoxy, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocycloalkyl, optionally substituted heteroaryl, halo,        carboxy, nitro, sulfonyl, sulfinyl, and optionally substituted        amino; and    -   for each occurrence, R₁₂ is independently chosen from alkyl        optionally substituted with one or more halo, alkoxy, halo,        nitro, heterocycloalkyl, and amino optionally substituted with        C(O)R_(a), wherein R_(a) is chosen from alkyl and optionally        substituted alkoxy;    -   each n is 0, 1 or 2; and    -   p is 0 or 1.

In another aspect, compounds of Formula III are provided:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein:

-   -   C is a nitrogen-containing heteroaryl ring chosen from        pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, pyrazolyl,        imidazolyl, and thiazolyl, each of which is optionally        substituted;    -   R₇, R₈, and R₉ are each independently chosen from hydrogen,        optionally substituted alkyl, and optionally substituted        alkenyl;    -   W is chosen from —N(R)SO₂R_(X)—, —SO₂N(R)R_(X)—, and        —N(R)COR_(X)—, wherein each R is independently chosen from        hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocycloalkyl, and heteroaryl, each of which, except for        hydrogen, is optionally substituted; and R_(X) is an bivalent        C₀-C₆alkylene, bivalent C₃-C₆cycloalkyl, or phenyl, each of        which is optionally substituted;    -   E is selected from C₅-C₆cycloalkyl, C₅-C₆heterocycle, phenyl,        wherein E is optionally substituted hydrogen, hydroxy,        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkoxy, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocycloalkyl, optionally substituted heteroaryl, halo,        carboxy, nitro, sulfonyl, sulfinyl, and optionally substituted        amino; and    -   D is an optionally substituted heterocycle.

In one embodiment, the compounds of Formula III are of the Formula IIIA:

wherein:

-   -   X₃ is selected from CH or N;    -   X₄ is selected from O, NH, or NR₇;    -   represents a single or double bond;    -   each R₇, R₈, and R₉ is independently chosen from hydrogen,        optionally substituted alkyl, and optionally substituted        alkenyl;    -   R₁₀ and R₁₁ are independently chosen from hydrogen, hydroxy,        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkoxy, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocycloalkyl, optionally substituted heteroaryl, halo,        carboxy, nitro, sulfonyl, sulfinyl, and optionally substituted        amino;    -   for each occurrence, R₁₂ is independently chosen from alkyl        optionally substituted with one or more halo, alkoxy, halo,        nitro, heterocycloalkyl, and amino optionally substituted with        C(O)R_(a), wherein R_(a) is chosen from alkyl and optionally        substituted alkoxy;    -   R_(X) is an bivalent C₄alkylene, bivalent C₆cycloalkyl, or        phenyl, each of which is optionally substituted; and    -   n is 0, 1, or 2.

In one aspect, compounds of Formula IV are provided:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is a heteroaryl selected from pyridine, pyrazine, pyridazine,        pyrimidine, 1,2,4-triazine or 1,3,5-triazine, optionally        substituted with halogen, hydroxyl group, —CF3 group, C1-C6        alkoxy group, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl group, wherein the number of        substituents does not exceed the number of available C—H bonds        of the heteroaryl; with multiple substitutions, each substituent        on the heteroaryl is chosen independent of the other        substituents;    -   G is an optionally substituted 5 membered heteroaryl selected        from thiophene, imidazole, pyrazole, thiazole, oxazole,        isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole;    -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is —S(O)n-(CH2)q-, —O—(CH2)q-, or —C(O)—(CH2)q-;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from

-   -   R13 is H, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl        or C3-C6 cycloalkyl;    -   R14, R15 and R16 are each independently H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles selected from pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are each independently H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl,        alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, —CF3; or R17 and        R18 can be taken together to form a 4 to 7 membered optionally        substituted ring containing 0-4 heteroatoms selected from N, O        or S;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

In another aspect, the compounds of Formula V are described:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is a heteroaryl selected from pyridine, pyrazine, pyridazine,        pyrimidine, 1,2,4-triazine or 1,3,5-triazine, optionally        substituted with halogen, hydroxyl group, —CF3 group, C1-C6        alkoxy group, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl group, wherein the number of        substituents does not exceed the number of available C—H bonds        of the heteroaryl; with multiple substitutions, each substituent        on the heteroaryl is chosen independent of the other        substituents;    -   G is an optionally substituted 5 membered heteroaryl selected        from thiophene, imidazole, pyrazole, thiazole, oxazole,        isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole;    -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is selected from —S(O)n-(CH2)q-, —O—CH2)q-, or —C(O)—(CH2)q;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from C3-C7 cycloalkyl optionally substituted with        two or more of R14, R15, and R16, C1-C6 straight or branched        optionally substituted alkyl,

-   -   R13 is selected from H, C1-C6 straight chain alkyl, C3-C6        branched chain alkyl or C3-C6 cycloalkyl;    -   R14, R15 and R16 can independently be H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles such as pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are independently selected from H, C1-C6        straight chain alkyl, C3-C6 branched chain alkyl, C3-C6        cycloalkyl, C1-C6 hydroxyalkyl, alkoxyalkyl in which the alkoxy        and alkyl portions each independently contain from 1 to 6 carbon        atoms, —CF3, or —C(O)O—, or R17 and R18 can be taken together to        form a 4 to 7 membered optionally substituted monocycloalkyl        ring or 8-14 bicycloalkyl ring, each optionally containing        between 1-3 heteroatoms selected from N, O or S, or;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

In one aspect, compounds of Formula VI are provided:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is selected from the group consisting of C3-C7 cycloalkyl        optionally substituted with two or more of R14, R15, and R16, or        C1-C6 straight or branched optionally substituted alkyl,

-   -   G is an optionally substituted 5 membered heteroaryl selected        from thiophene, imidazole, pyrazole, thiazole, oxazole,        isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole;    -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is —S(O)n-(CH2)q-, —O—(CH2)q-, or —C(O)—(CH2)q-;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from

-   -   R13 is H, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl        or C3-C6 cycloalkyl;    -   R14, R15 and R16 can independently be H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles such as pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are each independently be H, C1-C6 straight        chain alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl,        alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, —CF3; or R17 and        R18 can be taken together to form a 4 to 7 membered optionally        substituted ring that can contain additional heteroatoms such as        N, O or S;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

In some embodiments, the compounds of Formula IV are of the Formula IVa:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is a heteroaryl selected from pyridine, pyrazine, pyridazine,        pyrimidine, 1,2,4-triazine or 1,3,5-triazine, optionally        substituted with halogen, hydroxyl group, —CF3 group, C1-C6        alkoxy group, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl group, wherein the number of        substituents does not exceed the number of available C—H bonds        of the heteroaryl; with multiple substitutions, each substituent        on the heteroaryl is chosen independent of the other        substituents;    -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is —S(O)n-(CH2)q-, —O—(CH2)q-, or —C(O)—(CH2)q-;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from

-   -   R13 is H, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl        or C3-C6 cycloalkyl;    -   R20 is H, —CF₃, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl;    -   R14, R15 and R16 are each independently H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles selected from pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are each independently H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl,        alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, —CF3; or R17 and        R18 can be taken together to form a 4 to 7 membered optionally        substituted ring containing 0-4 heteroatoms selected from N, O        or S;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

In some embodiments, the compounds of Formula V are of the Formula Va:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is a heteroaryl selected from pyridine, pyrazine, pyridazine,        pyrimidine, 1,2,4-triazine or 1,3,5-triazine, optionally        substituted with halogen, hydroxyl group, —CF3 group, C1-C6        alkoxy group, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl group, wherein the number of        substituents does not exceed the number of available C—H bonds        of the heteroaryl; with multiple substitutions, each substituent        on the heteroaryl is chosen independent of the other        substituents;    -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is selected from —S(O)n-(CH2)q-, —O—(CH2)q-, or —C(O)—(CH2)q-;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from C3-C7 cycloalkyl optionally substituted with        two or more of R14, R15, and R16, C1-C6 straight or branched        optionally substituted alkyl,

-   -   R13 is selected from H, C1-C6 straight chain alkyl, C3-C6        branched chain alkyl or C3-C6 cycloalkyl;    -   R20 is selected from H, —CF3, C1-C6 straight chain alkyl, C3-C6        branched chain alkyl or C3-C6 cycloalkyl;    -   R14, R15 and R16 can independently be H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles such as pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are independently selected from H, C1-C6        straight chain alkyl, C3-C6 branched chain alkyl, C3-C6        cycloalkyl, C1-C6 hydroxyalkyl, alkoxyalkyl in which the alkoxy        and alkyl portions each independently contain from 1 to 6 carbon        atoms, —CF3, or —C(O)O—, or R17 and R18 can be taken together to        form a 4 to 7 membered optionally substituted monocycloalkyl        ring or 8-14 bicycloalkyl ring, each optionally containing        between 1-3 heteroatoms selected from N, O or S, or;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

In some embodiments, the compounds of Formula VI are of the Formula VIa:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein:    -   F is selected from the group consisting of C3-C7 cycloalkyl        optionally substituted with two or more of R14, R15, and R16, or        C1-C6 straight or branched optionally substituted alkyl,

-   -   m is an integer ranging from 0 to 3;    -   p is an integer ranging from 1 to 5;    -   H is —S(O)n-(CH2)q, —O—(CH2)q-, or —C(O)—(CH2)q-;    -   n is an integer ranging from 0 to 2;    -   q is an integer ranging from 0 to 5;    -   K is selected from

-   -   R13 is H, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl        or C3-C6 cycloalkyl;    -   R20 is H, —CF3, C1-C6 straight chain alkyl, C3-C6 branched chain        alkyl or C3-C6 cycloalkyl    -   R14, R15 and R16 can independently be H, C1-C6 straight chain        alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl, C1-C6        alkoxy, alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, alkoxyalkoxy in        which the alkoxy portions each independently contain from 1 to 6        carbon atoms, halogen, —OH, —NH2, —CF3, C1-C6 monoalkylamino,        C1-C6 dialkylamino, optionally substituted nitrogen containing        heterocycles such as pyrrolidine, piperidine, piperazine,        morpholine, thiomorpholine, azepane, 1,4-diazepane,        1,4-oxazepane and 1,4-thiazepane; or

-   -   wherein X can be a bond, O, S or NR19;    -   R17, R18 and R19 are each independently be H, C1-C6 straight        chain alkyl, C3-C6 branched chain alkyl, C1-C6 hydroxyalkyl,        alkoxyalkyl in which the alkoxy and alkyl portions each        independently contain from 1 to 6 carbon atoms, —CF3; or R17 and        R18 can be taken together to form a 4 to 7 membered optionally        substituted ring that can contain additional heteroatoms such as        N, O or S;    -   r is an integer ranging from 0 to 3;    -   t is an integer ranging from 1 to 2; and    -   u is an integer ranging from 1 to 6.

Also provided are pharmaceutical compositions comprising at least onecompound of Formulae I, II, III, IV, V, or VI and a pharmaceuticallyacceptable carrier.

Also provided are methods for treating diseases mediated by HIF-1αand/or HIF-2α.

Also provided are methods of targeting cells which express HIF-1α and/orHIF-2α.

Also provided are methods for treating diseases mediated by defectivepVHL protein.

Also provided are methods of targeting cells which have defective pVHLprotein.

The details of the invention are set forth in the accompanyingdescription below.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,illustrative methods and materials are now described. Other features,objects, and advantages of the invention will be apparent from thedescription and from the claims. In the specification and the appendedclaims, the singular forms also include the plural unless the contextclearly dictates otherwise. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. All patents and publications cited in this specification areincorporated herein by reference in their entireties.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the present specification, the following words, phrases, andsymbols are generally intended to have the meanings set forth below,except to the extent that the context in which they are used indicatedotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The compoundsand methods described herein may be useful for both human therapy andveterinary applications. In some embodiments, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to reducing the progression of a disease or disorder,either physically, e.g., stabilization of a discernible symptom,physiologically, e.g., stabilization of a physical parameter, or both.In yet another embodiment, “treatment” or “treating” refers to delayingthe onset of a disease or disorder.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

As used herein, “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, “parenteral administration” and “administeredparenterally” refer to modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, and intrasternal injection and infusion.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “alkyl” refers to refers to a saturated straight or branchedhydrocarbon, such as a straight or branched group of 1-20, 1-8, or 1-6carbon atoms, referred to herein as C₁-C₂₀ alkyl, C₁-C₈ alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groups include, but are not limitedto, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, and the like.

The term “alkenyl” refers to an unsaturated straight or branchedhydrocarbon having at least one carbon-carbon double bond, such as astraight or branched group of 2-20, 2-8, or 2-6 carbon atoms, referredto herein as (C₂-C₂₀) alkenyl, (C₂-C₈) alkenyl, and (C₂-C₆) alkenyl,respectively. Exemplary alkenyl groups include, but are not limited to,vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkynyl” refers to an unsaturated straight or branchedhydrocarbon having at least one carbon-carbon triple bond, such as astraight or branched group of 2-20, 2-8, or 2-6 carbon atoms, referredto herein as C₂-C₂₀ alkynyl, C₂-C₈ alkynyl, and C₂-C₆ alkynyl,respectively. Exemplary alkynyl groups include, but are not limited to,ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

“Cycloalkyl” refers to a saturated hydrocarbon ring group, having thespecified number of carbon atoms, such as, for example from 3 to 7 ringcarbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and cagedsaturated ring groups such as, for example, adamantane.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-20,1-8, or 1-6 carbon atoms, referred to herein as (C₁-C₂₀) alkoxy, (C₁-C₈)alkoxy, and (C₁-C₆) alkoxy, respectively. Exemplary alkoxy groupsinclude, but are not limited to methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like.

“Acyl” refers to the groups (alkyl)-C(O)—, (cycloalkyl)-C(O)—,(aryl)-C(O)—, (heteroaryl)-C(O)—, and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

“Alkoxycarbonyl” refers to an ester group of the formula (alkoxy)(C═O)—attached through the carbonyl carbon wherein the alkoxy group has theindicated number of carbon atoms. Thus, a C₁-C₆ alkoxycarbonyl group isan alkoxy group having from 1 to 6 carbon atoms attached through itsoxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Aryl” encompasses: 5- and 6-membered carbocyclic aromatic rings, forexample, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene.

For example, aryl includes 5- and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered heterocycloalkyl ring containing 1 or moreheteroatoms chosen from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the point of attachment may be at the carbocyclic aromatic ring or theheterocycloalkyl ring. Bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Bivalent radicals derived from univalentpolycyclic hydrocarbon radicals whose names end in “-yl” by removal ofone hydrogen atom from the carbon atom with the free valence are namedby adding “-idene” to the name of the corresponding univalent radical,e.g., a naphthyl group with two points of attachment is termednaphthylidene. Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with a heterocycloalkyl aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Heteroaryl” encompasses: 5- to 7-membered aromatic, monocyclic ringscontaining one or more, for example, from 1 to 4, or In someembodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with theremaining ring atoms being carbon; and bicyclic heterocycloalkyl ringscontaining one or more, for example, from 1 to 4, or In someembodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with theremaining ring atoms being carbon and wherein at least one heteroatom ispresent in an aromatic ring. For example, heteroaryl includes a 5- to7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-memberedcycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, thepoint of attachment may be at the heteroaromatic ring or the cycloalkylring. When the total number of S and O atoms in the heteroaryl groupexceeds 1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1. Examples ofheteroaryl groups include, but are not limited to, (as numbered from thelinkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyrimidinyl, 3-pyrazolinyl, 2-thiazolyl, imidazolinyl,isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl,thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl,indolinyl, pyridizinyl, triazolyl, quinolinyl, and pyrazolyl. Bivalentradicals derived from univalent heteroaryl radicals whose names end in“-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a pyridyl group with two points of attachmentis a pyridylidene. Heteroaryl does not encompass or overlap with aryl asdefined herein. Substituted heteroaryl also includes ring systemssubstituted with one or more oxide (—O⁻) substituents, such as pyridinylN-oxides.

“Heterocycle” refers to a single aliphatic ring, containing at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms.

Suitable heterocycloalkyl groups include, for example (as numbered fromthe linkage position assigned priority 1), 2-pyrrolinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl,4-piperdyl, and 2,5-piperzinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo moieties,such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

The term “cyano” as used herein refers to —CN.

The term “carboxy” as used herein refers to —COOH or its correspondingcarboxylate salts (e.g., —COONa). The term carboxy also includes“carboxycarbonyl,” for example, a carboxy group attached to a carbonylgroup, for example, —C(O)—COOH or salts, such as —C(O)—COONa.

The term “nitro” refers to —NO₂.

The term “hydroxy” and “hydroxyl” refer to —OH.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, alkenyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl (including “substituted” pyridinyl,pyrimidinyl, pyrazinyl, quinolinyl, pyrazolyl, and thiazolyl”), unlessotherwise expressly defined, refer respectively to alkyl, alkenyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more(such as up to 5, for example, up to 3) hydrogen atoms are replaced by asubstituent independently chosen from:

-   -   —R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b)R^(c), halo, cyano, oxo (as a substituent for        heterocycloalkyl), nitro, —COR^(b), —CO₂R^(b), —CONR^(b)R^(c),        —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), —NR^(c)COR^(b),        —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a), —SO₂R^(a),        —SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),    -   where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted C₂-C₆ alkenyl, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocycloalkyl, and optionally substituted heteroaryl;    -   R^(b) is chosen from hydrogen, optionally substituted C₁-C₆        alkyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heterocycloalkyl, and optionally        substituted heteroaryl; and    -   R^(c) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b) and R^(c), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂ (C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂ (C₁-C₄ haloalkyl).

In some embodiments, the terms “substituted” alkyl, alkenyl, cycloalkyl,aryl, heterocycloalkyl, and heteroaryl (including “substituted”pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, pyrazolyl, andthiazolyl”), unless otherwise expressly defined, refer respectively toalkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, and heteroarylwherein one or more (such as up to 5, for example, up to 3) hydrogenatoms are replaced by a substituent independently chosen from: —R^(a),—OR^(b), —COR^(b), —CO₂R^(b), NO₂, —NR^(b)R^(c), —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(c)SO₂R^(a) and CN, whereR^(a), R^(b), and R^(c) are as described herein.

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—, (substituted cycloalkyl)-C(O)—, (substituted aryl)-C(O)—,(substituted heteroaryl)-C(O)—, and (substitutedheterocycloalkyl)-C(O)—, wherein substituted alkyl, substitutedcycloalkyl, substituted aryl, substituted heteroaryl, and substitutedheterocycloalkyl are as described herein. In some embodiments, the term“substituted acyl” refers to the groups (substituted alkyl)-C(O)—,(substituted aryl)-C(O)—, and (substituted heteroaryl)-C(O)—, whereinsubstituted alkyl, substituted aryl, and substituted heteroaryl are asdescribed herein.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein “substituted alkyl” is asdescribed herein.

The term “substituted cycloalkyloxy” refers to cycloalkyloxy wherein thecycloalkyl constituent is substituted (i.e., —O-(substitutedcycloalkyl)) wherein “substituted cycloalkyl” is as described herein.

The term “substituted amino” refers to the group —NR^(b)R^(c),—NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), and—NR^(c)SO₂R^(a), wherein R^(b) and R^(c) are as described herein. Theterm “substituted amino” also refers to N-oxides of the groups —NHR^(d),and NR^(d)R^(d) each as described herein. N-oxides can be prepared bytreatment of the corresponding amino group with, for example, hydrogenperoxide or m-chloroperoxybenzoic acid. The person skilled in the art isfamiliar with reaction conditions for carrying out the N-oxidation.

The term “substituted aryloxy” refers to aryloxy wherein the arylconstituent is substituted (i.e., —O-(substituted aryl)) wherein“substituted aryl” is as described herein.

Compounds described herein include, but are not limited to, anystereoisomer, tautomer, rotomer, deuterated analogues, and/orpharmaceutically acceptable salt as defined herein.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated.

Compounds that contain asymmetrically substituted carbon atoms can beisolated in optically active or racemic forms. Methods on how to prepareoptically active forms from optically active starting materials areknown in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. The processes described herein can bestereoselective such that any given reaction starting with one or morechiral reagents enriched in one stereoisomer forms a product that isalso enriched in one stereoisomer. The reaction can be conducted suchthat the product of the reaction substantially retains one or morechiral centers present in the starting materials. The reaction can alsobe conducted such that the product of the reaction contains a chiralcenter that is substantially inverted relative to a corresponding chiralcenter present in the starting materials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalcrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid,diacetyltartaric-acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid or the various optically active camphorsulfonic acidssuch as β-camphorsulfonic acid. Resolution of racemic mixtures can alsobe carried out by elution on a column packed with an optically activeresolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elutionsolvent composition can be determined by one skilled in the art.

Compounds as described herein can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The compounds disclosed herein can be used in different enrichedisotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C, ¹⁴C,and or ¹⁸F. In one particular embodiment, the compounds are deuterated.Such deuterated forms can be made by the procedure described in U.S.Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos.5,846,514 and 6,334,997, deuteration can improve the efficacy andincrease the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp.;Kabalka, George W. and Varma, Rajender S. The Synthesis of RadiolabeledCompounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21),6601-21, Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Compounds as described herein can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Compounds as described herein also include crystalline and amorphousforms of those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form,” “polymorph,”and “novel form” may be used interchangeably herein, and are meant toinclude all crystalline and amorphous forms of the compound, including,for example, polymorphs, pseudopolymorphs, solvates, hydrates,unsolvated polymorphs (including anhydrates), conformational polymorphs,and amorphous forms, as well as mixtures thereof, unless a particularcrystalline or amorphous form is referred to. Compounds as describedherein also include pharmaceutically acceptable forms of the recitedcompounds, including chelates, non-covalent complexes, pharmaceuticallyacceptable prodrugs, and mixtures thereof.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “salts” includes solvates of salts. Similarly, “salts”includes solvates of salts. Suitable solvates are pharmaceuticallyacceptable solvates, such as hydrates, including monohydrates andhemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”.

Provided herein are compounds of Formula I:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers and stereoisomers thereof;    -   wherein:    -   A, B, X, B, R₁, R₂, R₃, R₄, R₅, and R₆, are as defined above for        Formula I;    -   provided that if A is 3-pyridinyl, X is CH₂NH, R₁, R₂, and R₄        are each hydrogen, R₃ is Me, and Y is O, then B is not phenyl or        4-methylphenyl.

In some embodiments, A is chosen from 2-pyrazinyl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 2-imidazolyl, and 5-imidazolyl, each of whichis optionally substituted.

In some embodiments, A is chosen from 2-pyrazinyl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, (1-methyl)-2-imidazolyl, and(1-methyl)-5-imidazolyl.

In some embodiments, A is chosen from 2-pyridinyl, 3-pyridinyl, and4-pyridinyl.

In some embodiments, A is 3-pyridinyl.

In some embodiments, R₁ is chosen from hydrogen and optionallysubstituted alkyl.

-   -   In some embodiments, R₁ is chosen from hydrogen and lower alkyl.    -   In some embodiments, R₁ is hydrogen or methyl.    -   In some embodiments, R₁ is hydrogen.

In some embodiments, R₂, R₃ and R₄ are each independently chosen fromhydrogen and optionally substituted alkyl.

In some embodiments, R₂ is hydrogen.

In some embodiments, R₃ is chosen from hydrogen and lower alkyl.

In some embodiments, R₃ is hydrogen or methyl.

In some embodiments, R₄ is chosen from hydrogen and lower alkyl.

In some embodiments, R₄ is hydrogen.

In some embodiments, X is chosen from CH₂CH₂NR, CH₂NR, or NR.

In some embodiments, R is chosen from hydrogen and lower alkyl.

In some embodiments, R is hydrogen.

In some embodiments, Y is chosen from O, S, or NR.

In some embodiments, R is chosen from hydrogen and lower alkyl.

In some embodiments, R is hydrogen.

In some embodiments, R is O.

In some embodiments, R is S.

In some embodiments, B is phenyl optionally substituted with one or moregroups chosen from halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, aryloxy, acyl, carboxy,alkoxycarbonyl, NO₂, optionally substituted amino, and CN, wherein eachof said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, alkoxy, and aryloxy groups may be optionallyindependently substituted with one or more groups chosen from halo,alkyl, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, heterocycloalkyl, andoptionally substituted amino.

In some embodiments, B is phenyl optionally substituted with one or moregroups chosen from optionally substituted amino, halo, and lower alkyloptionally substituted with optionally substituted amino,heterocycloalkyl, alkoxy, or hydroxyl.

In some embodiments, B is phenyl optionally substituted with one or moregroups chosen from halo, optionally substituted amino and lower alkyloptionally substituted with optionally substituted amino orheterocycloalkyl.

In some embodiments, B is chosen from phenyl, 3-methylphenyl,3-methoxyphenyl, 4-chlorophenyl, 4-tert-butylphenyl, 4-bromophenyl,4-fluorophenyl, 4-methoxyphenyl, 4-(4-methylpiperazinyl)phenyl,4-morpholinylphenyl, 3,5-dimethylphenyl, 2,4-dimethylphenyl,3,4-dimethoxyphenyl.

In other illustrative embodiments, compounds of Formula I are as setforth below:

-   4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinyl)benzamide;-   4-(5-Methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinyl)benzamide;-   N-Methyl-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinyl)benzamide;-   4-(5-Methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyridinylmethyl)benzamide;-   4-(5-Methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(5-Methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinylmethyl)benzamide;-   N-Methyl-4-(5-methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(5-Methyl-4{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-[2-(3-pyridinyl)ethyl]benzamide;-   4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyrazinylmethyl)benzamide;-   N-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide;-   N-[(1-Methyl-1H-imidazol-5-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide;-   4-{5-Methyl-4-[phenylsulfonyl)methyl]-1,3-oxazol-2-yl}-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-Chlorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-tert-Butylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(3,5-Dimethylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(5-Methyl-4-{[(3-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-Methoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(5-Methyl-4-{[(3-methoxyphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(3,4-Dimethoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(5-Methyl-4-{[(2,4-dimethylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-Fluorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide;-   4-[5-Methyl-4-({[4-(4-methyl-1-piperazinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide;-   4-[5-Methyl-4-({[4-(4-morpholinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide;-   4-(4-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-thiazol-2-yl)-N-(3-pyridinylmethyl)benzamide;    or a pharmaceutically acceptable salt thereof.

Described herein are compounds of Formula II:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein C, R₇, R₈, R₉, R₁₀, W, and D are as defined above for FormulaII.

In some embodiments, C is chosen from 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyrimidinyl, 3-pyrazolinyl, imidazolinyl, isoxazolinyl,oxazolinyl, thiadiazolinyl, thiazole, tetrazolyl, benzoimidazolinyl,indolinyl, pyridizinyl, triazolyl, quinolinyl, and pyrazolyl, each ofwhich is optionally substituted. In some embodiments, A is chosen from3-pyrazolyl, 3-quinolinyl, 5-quinolinyl, 2-pyrazinyl, 2-pyrimidinyl,2-pyridinyl, 3-pyridinyl, and 4-pyridinyl. In some embodiments, A ischosen from 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl. In someembodiments, A is 3-pyridinyl.

In some embodiments, C is

wherein

-   -   n is 0, 1 or 2;    -   for each occurrence, R₁₂ is independently chosen from alkyl        optionally substituted with one or more halo, alkoxy, halo,        nitro, heterocycloalkyl, and amino optionally substituted with        C(O)R_(a), wherein R_(a) is chosen from alkyl and optionally        substituted alkoxy; and    -   X₁ and X₂ are each independently chosen from N, NO, and CH,        provided that at least one of X₁ and X₂ is not CH.

In some embodiments, X₁ is N and X₂ is CH.

In some embodiments, for each occurrence, R₁₂ is independently chosenfrom methyl, methoxy, halo, nitro, morpholino, trifluoromethyl, andNHC(O)Me.

In some embodiments, n is 0.

In some embodiments, R₇ is chosen from hydrogen and optionallysubstituted alkyl. In some embodiments, R₇ is chosen from hydrogen andlower alkyl. In some embodiments, R₇ is hydrogen or methyl. In someembodiments, R₇ is hydrogen.

In some embodiments, R₈ and R₉ are each independently chosen fromhydrogen and optionally substituted alkyl. In some embodiments, R₈ ishydrogen.

In some embodiments, R₉ is chosen from hydrogen and lower alkyl. In someembodiments, R₉ is hydrogen.

In some embodiments, R₁₀ is chosen from hydrogen, hydroxy, lower alkyl,lower alkoxy, halo, carboxy, and nitro. In some embodiments, R₁₀ ischosen from hydrogen, methyl, halo, and nitro. In some embodiments, R₁₀is chosen from hydrogen and lower alkyl. In some embodiments, R₁₀ ishydrogen.

In some embodiments, W is —NRSO₂. In some embodiments, W is —NRCO—. Insome embodiments, W is SO₂NR—.

In some embodiments, R is chosen from hydrogen and lower alkyl. In someembodiments, R is hydrogen.

In some embodiments, D is pyridyl, pyrazinyl, pyrimidinyl, pyrazolinyl,thiazolyl, imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl,thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,benzofuranyl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl,quinolinyl, and pyrazolyl.

In some embodiments, D is an optionally substituted pyridyl ring.

In some embodiments, D is pyridyl optionally substituted with one ormore groups chosen from halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, aryloxy, acyl, carboxy,alkoxycarbonyl, NO₂, optionally substituted amino, and CN, wherein eachof said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, alkoxy, and aryloxy groups may be optionallyindependently substituted with one or more groups chosen from halo,alkyl, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, heterocycloalkyl, andoptionally substituted amino.

In some embodiments, D is pyridyl optionally substituted with one ormore groups chosen from optionally substituted amino, halo, and loweralkyl optionally substituted with optionally substituted amino,heterocycloalkyl, alkoxy, or hydroxyl.

In some embodiments, D is pyridyl optionally substituted with one ormore groups chosen from halo, optionally substituted amino and loweralkyl optionally substituted with optionally substituted amino orheterocycloalkyl.

In some embodiments, D is chosen from pyridyl, 2-methylpyridyl,2-fluoropyridyl, 2-chloropyridyl, 2-bromopyridyl,2-methoxycarbonylpyridyl, 2-trifluoromethylpyridyl, 2-cyanopyridyl,3-aminopyridyl, 3-methoxypyridyl, 3-methylpyridyl, 3-fluoropyridyl,3-chloropyridyl, 3-bromopyridyl, 3-trifluoromethylpyridyl,tert-butylpyridyl, 4-ethynylpyridyl, 3-cyanopyridyl, 3-nitropyridyl,3-pyridylpyridyl, 3-(2-pyrimidinyl)pyridyl,3-(1-methyl-1H-pyrazol-3-yl)pyridyl,3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridyl,3-(5-methyl-1,2,4-oxadiazol-2-yl)pyridyl,3-(2-methyl-1,3-thiazol-4-yl)pyridyl, 4-aminopyridyl, 4-methoxypyridyl,4-butoxypyridyl, 4-phenoxypyridyl, 4-methylpyridyl, 4-propylpyridyl,4-tert-butylpyridyl, 4-(1-adamantyl)pyridyl,4-(3-chloro-1-adamantyl)pyridyl, 4-methoxycarbonylethylpyridyl,4-acetamidopyridyl, 4-fluoropyridyl, 4-chloropyridyl, 4-bromopyridyl,4-iodopyridyl, 4-trifluoromethoxypyridyl, 4-methoxycarbonylpyridyl,4-acetylpyridyl, 4-trifluoromethylpyridyl, 4-cyanopyridyl,4-nitropyridyl, 4′-methoxy[1,1′-bipyridyl]-4-yl,4′-methyl[1,1′-bipyridyl]-4-yl, 4-pyridylpyridyl,4′-fluoro[1,1′-bipyridyl]-4-yl, 4′-chloro[1,1′-bipyridyl]-4-yl,4-(2-pyrimidinyl)pyridyl, 4-(1H-pyrazol-1-yl)pyridyl,4-(2-methyl-1,3-thiazol-4-yl)pyridyl, 4-(1,3-oxazol-5-yl)pyridyl,3,4-dimethoxypyridyl, 3-tert-butyl-4-methoxypyridyl,2,3,4,5,6-pentamethylpyridyl, 2,4-dimethylpyridyl, 3,4-dimethylpyridyl,3,5-dimethylpyridyl, 3-fluoro-4-methylpyridyl, 3-chloro-2-methylpyridyl,3-chloro-4-methylpyridyl, 3,4-dichloropyridyl, 3-cyano-4-fluoropyridyl,2-naphthalenyl, 5-(dimethylamino)-2-naphthalenyl,2,3-dihydro-5-indeneyl, 2-(dimethylamino)-2,3-dihydro-5-indeneyl,4-(4-methylpiperazin-1-yl)pyridyl, 4-(dimethylamino)methylphenyl,4-(diethylamino)methylphenyl, 4-(dipropylamino)methylphenyl,4-(1-pyrrolidinylmethyl)phenyl, 4-(1-piperidinylmethyl)phenyl,4-(1-azepanylmethyl)phenyl, 4-(4-morpholinylmethyl)phenyl,4-(4-methoxy-1-piperidinyl)methylphenyl,4-(4-methyl-1-piperazinyl)methylphenyl, 4-(3-hydroxypropyl)phenyl,3-morpholinophenyl, 4-morpholinophenyl, 4-(1-piperidinyl)pyridyl,(4-methoxy-1-piperidinyl)pyridyl,(21-amino-4,7,10,13,16,19-hexaoxahenicos-1-yl)pyridyl,{[3-(4-morpholinyl)propyl]amino}pyridyl,3-(4-methyl-1-piperazinyl)pyridyl,4-{[2-(dimethylamino)ethyl]amino}pyridyl, 3′-(trifluoromethyl)[1,1′-bipyridyl], 4-benzylpyridyl,4-[3-(4-morpholinyl)-1-propynyl]pyridyl,4-[3-(dimethylamino)-1-propynyl]pyridyl,4-[3-(4-morpholinyl)propyl]pyridyl, 4-[3-(dimethylamino)propyl]pyridyl,3-(propionylamino)pyridyl, and 3-(acryloylamino)pyridyl.

In some embodiments, D is chosen from 3-fluoropyridyl, 3-chloropyridyl,3-bromopyridyl, 3-(2-pyrimidinyl)pyridyl,3-(1-methyl-1H-pyrazol-3-yl)pyridyl,3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridyl,3-(5-methyl-1,2,4-oxadiazol-2-yl)pyridyl,4-butoxypyridyl-4-tert-butylpyridyl, 4-(2-pyrimidinyl)pyridyl,3,4-dimethoxypyridyl, 3-tert-butyl-4-methoxypyridyl,3,4-dimethylpyridyl, 3,5-dimethylpyridyl, 3-fluoro-4-methylpyridyl,3-chloro-4-methylpyridyl, 2-(dimethylamino)-2,3-dihydro-5-indeneyl,4-(4-methylpiperazin-1-yl)pyridyl, 4-(dimethylamino)methylpyridyl,4-(diethylamino)methylpyridyl, 4-(dipropylamino)methylpyridyl,4-(1-pyrrolidinylmethyl)pyridyl, 4-(1-piperidinylmethyl)pyridyl,4-(1-azepanylmethyl)pyridyl, 4-(4-morpholinylmethyl)pyridyl,4-(4-methoxy-1-piperidinyl)methylpyridyl,4-(4-methyl-1-piperazinyl)methylpyridyl, and 4-(3-hydroxypropyl)pyridyl.

In some embodiments, the radical

is attached to the phenyl ring at the 3 position. In some embodiments,the radical

is attached to the phenyl ring at the 4 position.

In other illustrative embodiments, compounds of Formula II and IIA areas set forth below:

-   N-(3-Pyridinyl)-4{[(3-pyridylsulfonyl)amino]methyl}benzamide II-1;-   4-({[(6-Chloro-3-pyridinyl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamide    II-2;-   4-({[(6-Phenoxy-3-pyridinyl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamide    II-3;-   N-(3-Pyridinyl)-4{[(2-thienylsulfonyl)amino]methyl}benzamide II-4;-   N-(3-Pyridinyl)-4{[(3-thienylsulfonyl)amino]methyl}benzamide II-5;-   4-({[(1,2-Dimethyl-1H-imidazol-5-yl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamide    II-6;-   N-(3-pyridinyl)-4-{[(4H-1,2,4-triazol-3-ylsulfonyl)amino]methyl}benzamide    II-7; and-   N-(3-Pyridinyl)-4-{[(2-furanylsulfonyl)amino]methyl}benzamide II-8.

Also described herein are compounds of Formula III:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein C, E, D, R₇, R₈, R₉, and W are as described above for FormulaIII.

In some embodiments, A is chosen from 2-thiazolyl, 3-pyrazolyl,3-quinolinyl, 5-quinolinyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridinyl,3-pyridinyl, and 4-pyridinyl, each of which is optionally substituted.In some embodiments, A is chosen from 2-thiazolyl, 3-pyrazolyl,3-quinolinyl, 5-quinolinyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridinyl,3-pyridinyl, and 4-pyridinyl. In some embodiments, A is chosen from2-pyridinyl, 3-pyridinyl, and 4-pyridinyl. In some embodiments, A is3-pyridinyl.

In some embodiments, C is

whereinn is 0, 1 or 2;for each occurrence, R₁₂ is independently chosen from alkyl optionallysubstituted with one or more halo, alkoxy, halo, nitro,heterocycloalkyl, and amino optionally substituted with C(O)R_(a),wherein R_(a) is chosen from alkyl and optionally substituted alkoxy;andX₁ and X₂ are each independently chosen from N, NO, and CH, providedthat at least one of X₁ and X₂ is not CH.

In some embodiments, X₁ is N and X₂ is CH.

In some embodiments, for each occurrence, R₅ is independently chosenfrom methyl, methoxy, halo, nitro, morpholino, trifluoromethyl, andNHC(O)Me.

In some embodiments, n is 0.

In some embodiments, R₇ is chosen from hydrogen and optionallysubstituted alkyl.

In some embodiments, R₇ is chosen from hydrogen and lower alkyl. In someembodiments, R₇ is hydrogen or methyl. In some embodiments, R₇ ishydrogen.

In some embodiments, R₈ and R₉ are each independently chosen fromhydrogen and optionally substituted alkyl. In some embodiments, R₈ ishydrogen.

In some embodiments, R₉ is chosen from hydrogen and lower alkyl. In someembodiments, R₉ is hydrogen.

In some embodiments, W is —N(R)SO₂R_(X)—. In some embodiments, W is—SO₂N(R)R_(X)—. In some embodiments, W is —N(R)COR_(X)—.

In some embodiments, R is chosen from hydrogen and lower alkyl. In someembodiments, R is hydrogen.

In some embodiments, R_(X) is an optionally substituted bivalentC₀-C₆alkylene. In certain embodiments, the bivalent C₀-C₆alkylene is C₄alkylene. In other embodiments, R_(X) is optionally substituted bivalentC₃-C₆cycloalkyl. In certain embodiments, the bivalent C₃-C₆cycloalkyl isC₆cycloalkyl. In other embodiments, R_(X) is optionally substitutedphenyl.

In some embodiments, E is a C₅-C₆cycloalkyl. In some embodiments, theC₅-C₆cycloalkyl is C₆cycloalkyl. In some embodiments, E is aC₅-C₆heterocyle. In some embodiments, E is phenyl.

In another aspect, compounds of Formula IIIA are provided:

wherein: X₃ X₄,

, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and Rx are as defined above for FormulaIIIA

In some embodiments, X3 is CH. In some embodiments, X3 is N.

In some embodiments, X₄ is NH. In some embodiments, X₄ is NR₇ and R₇ isC₁alkyl.

In some embodiments, R_(X) is a bivalent C₄alkylene. In someembodiments, R_(X) is a bivalent C₆cycloalkyl. In some embodiments,R_(X) is phenyl.

In some embodiments, all three

represent single bonds. In some embodiments, all three

represent double bonds.

In another illustrative embodiment, a compound of Formula III andFormula IIIA is as set forth below:

-   4-((4-(4-methylpiperazin-1-yl)cyclohexanesulfonamido)methyl)-N-(pyridin-3-yl)benzamide    III-1.

Described herein are compounds of Formula IV:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein F, G, H, K, R₁₃, m and p are as defined above for        Formula IV.

In some embodiments, F is chosen from 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyrimidinyl, 3-pyrazolinyl, imidazolinyl, triazolyl, andpyrazolyl, each of which is optionally substituted. In some embodiments,A is chosen from 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridinyl,3-pyridinyl, and 4-pyridinyl. In some embodiments, A is chosen from2-pyridinyl, 3-pyridinyl, and 4-pyridinyl. In some embodiments, A is3-pyridinyl.

In some embodiments, G is selected from imidazole, pyrazole, andtriazole.

In some embodiments, G is selected from oxazole, isoxazole, andoxadiazole.

In some embodiments, G is selected from thiophene, thiazole,isothiazole, and thiadiazole.

In some embodiments, H is —S(O)n-(CH2)q-.

In some embodiments, H is —S(O)₂.

In some embodiments, K is

In some embodiments, K is

In another aspect, the compounds of Formula V are described:

-   -   and pharmaceutically acceptable salts, hydrates, solvates,        prodrugs, enantiomers, and stereoisomers thereof;    -   wherein F, G, H, K, R₁₃, m and p are as defined above for        Formula V.

In some embodiments, F is chosen from 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyrimidinyl, 3-pyrazolinyl, imidazolinyl, triazolyl, andpyrazolyl, each of which is optionally substituted. In some embodiments,F is chosen from 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridinyl,3-pyridinyl, and 4-pyridinyl. In some embodiments, F is chosen from2-pyridinyl, 3-pyridinyl, and 4-pyridinyl. In some embodiments, F is3-pyridinyl.

In some embodiments, G is selected from imidazole, pyrazole, andtriazole.

In some embodiments, G is selected from oxazole, isoxazole, andoxadiazole.

In some embodiments, G is selected from thiophene, thiazole,isothiazole, and thiadiazole.

In some embodiments, H is —S(O)n-(CH2)q-.

In some embodiments, H is —S(O)₂.

In some embodiments, K is C3-C7 cycloalkyl optionally substituted withtwo or more of R14, R15, and R16.

In some embodiments, K is C1-C6 straight or branched optionallysubstituted alkyl.

In some embodiments, K is,

In some embodiments, K is,

In some embodiments, K is,

In some embodiments, K is,

In some embodiments, K is,

In some embodiments, K is,

In one aspect, compounds of Formula VI are provided:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

-   -   wherein F, G, H, K, R₁₃, m and p are as defined above for        Formula VI.

In some embodiments, F is C3-C7 cycloalkyl optionally substituted withtwo or more of R14, R15, and R16.

In some embodiments, F is C1-C6 straight or branched optionallysubstituted alkyl.

In some embodiments, F is

In some embodiments, F is

In some embodiments, F is

In some embodiments, F is

In some embodiments, F is

In some embodiments, F is

In some embodiments, G is selected from imidazole, pyrazole, andtriazole.

In some embodiments, G is selected from oxazole, isoxazole, andoxadiazole.

In some embodiments, G is selected from thiophene, thiazole,isothiazole, and thiadiazole.

In some embodiments, H is —S(O)n-(CH2)q-.

In some embodiments, H is —S(O)2.

In some embodiments, K is

In some embodiments, K is

In other illustrative embodiments, compounds of Formula IV, V, and VIare as set forth below:

-   5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridine-3-ylmethyl)benzamide;-   (4-(5-methyl-4-((1-methylpiperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide);-   4-(4-((1-isobutylpiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-(4-[[(4-aminocyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[4-([[(1S,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[(1S,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[(1S,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[4-([[(1R,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[(1R,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-[5-methyl-4-([[(1R,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide;-   4-(4-((1-tert-butylpiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(5-methyl-4-((1-neopentylpiperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(4-((1-isobutylpiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(4-(((2S,6R)-1-isobutyl-2,6-dimethylpiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(4-(((2S,6R)-2,6-dimethylpiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(5-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(4-((1-isobutyl-2-oxopiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(4-((1-isobutyl-2,6-dioxopiperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide;    and-   4-(4-((4-isobutylpiperidin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide.

Other illustrative compounds of the above Formulae are described below:

-   4-(5-methyl-4-((piperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(5-methyl-4-((4-methylpiperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-((4-isobutylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-((4-tert-butylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-((4-cyclopropylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(5-methyl-4-((4-(2,2,2-trifluoroethyl)piperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(5-methyl-4-(morpholinosulfonylmethypoxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-((4-isopropylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(5-methyl-4-(((4-neopentylpiperazin-1-yl)sulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-(((4-ethylpiperazin-1-yl)sulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(4-((((4-cyclobutylpiperazin-1-yl)sulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

-   4-(5-methyl-4-((thiomorpholinosulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

Methods for obtaining the compounds and pharmaceutically acceptablesalts described herein will be apparent to those of ordinary skill inthe art, suitable procedures being described, for example, in thereaction schemes and examples below, and the references cited herein.

Referring to Reaction Scheme 1, Step 1, a compound of Formula 101, iscombined with compound 100 in the presence of an acid (such as gaseousHCl) to give a compound of Formula 102, which is isolated and optionallypurified.

Referring to Reaction Scheme 1, Step 2, a mixture of a compound ofFormula 102 is combined with a chlorinating agent (such as POCl₃) in anorganic solvent to give the product, a compound of Formula 103, which isisolated and optionally purified.

Referring to Reaction Scheme 1, Step 3, a mixture of a compound ofFormula 103 is combined with a arylsulfinic acid and a base, or with thesalt of the arylsulfinic acid, in a polar organic solvent (such as DMFand/or THF) to give the product, a compound of Formula 104, which isisolated and optionally purified.

Referring to Reaction Scheme 1, Step 3, an alternative preparation maybe achieved by treating a mixture of compound 103 with an arylthiol andan inorganic base (such as K₂CO₃) in a polar organic solvent (such asDMF). This mixture is subsequently treated with an oxidizing agent (suchas meta-chloroperbenzoic acid) to give the product, a compound ofFormula 104, which is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 4, a compound of Formula 104 istreated with an acidic solution (such as hydrochloric acid), oralternatively is treated with a basic solution (such as sodium hydroxidesolution) to provide a compound of Formula 105, which is isolated andoptionally purified.

Referring to Reaction Scheme 1, Step 5, a mixture of a compound ofFormula 105 is combined with a halogenating agent (such as oxalylchloride), to give an acid chloride, or reacted with other reagents toadd other suitable leaving groups. This intermediate is combined with anorganic base (such as pyridine), in a polar organic solvent (such as DMFand/or THF). An amine is then added to give the product, a compound ofFormula 106, which is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 6, a mixture of a compound ofFormula 104 is treated with an acidic solution (such as hydrochloricacid), or alternatively is treated with a basic solution (such as sodiumhydroxide solution) to provide a compound of Formula 107, which isisolated and optionally purified.

Referring to Reaction Scheme 2, Step 7, a mixture of a compound ofFormula 107 is combined with a coupling reagentsuch as HBTU and treatedwith the appropriate amine in a polar organic solvent (such as DMFand/or THF) and in the presence of a base such as DIEAThe product, acompound of Formula 108, is isolated and optionally purified. Product108 is then reacted first with MsCl in the presence of a base such asNEt₃ in a polar organic solvent (such as DMF and/or THF) andsubsequently treated with an arylthiol, in the presence of a base suchas K₂CO₃. The intermediate sulfide is isolated and the crude product istreated with xone in MeOH, to give the product, a compound of formula106 which is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 8, a mixture of a compound ofFormula 109 is treated with a thiating agent (such as O,O-diethylhydrogen dithiophosphate) to give a compound of Formula 110, which isisolated and optionally purified.

Referring to Reaction Scheme 3, Step 9, a mixture of a compound ofFormula 110 is treated with a dichloroketone (such as dichloroacetone)in a polar organic solvent (such as DMF) to give to provide a compoundof Formula III, which is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 10, a mixture of a compound ofFormula III is combined with an arylsulfinic acid and a base, or withthe salt of the arylsulfinic acid, in a polar organic solvent (such asDMF and/or THF) to give the product, a compound of Formula 112, which isisolated and optionally purified.

Referring to Reaction Scheme 3, Step 10, an alternative preparation maybe achieved by treating a mixture of compound III with an arylthiol andan inorganic base (such as K₂CO₃) in a polar organic solvent (such asDMF). This mixture is subsequently treated with an oxidizing agent (suchas meta-chloroperbenzoic acid) to give the product, a compound ofFormula 112, which is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 11, a mixture of a compound ofFormula 112 is treated with an acidic solution (such as hydrochloricacid), or alternatively is treated with a basic solution (such as sodiumhydroxide solution) to provide a compound of Formula 113, which isisolated and optionally purified.

Referring to Reaction Scheme 3, Step 12, a mixture of a compound ofFormula 113 is combined with a halogenating agent (such as oxalylchloride), to give an acid chloride, or other reagents to add othersuitable leaving groups (such as HBTU). This intermediate is combinedwith an organic base (such as pyridine), in a polar organic solvent(such as DMF and/or THF). An amine is then added to give the product, acompound of Formula 114, which is isolated and optionally purified.

wherein C, D, R, R₇, R₈, R₉, R₁₀, and W are as defined above for FormulaIII.

Referring to Reaction Scheme 1, Step 1, a compound of Formula 1, iscombined with an aqueous solution of base (such as NaOH in water), andtreated with a compound of Formula 2, where P is a nitrogen protectinggroup (such as benzenesulfonyl), and L is a leaving group (such asbromide), to give a compound of Formula 3, which is isolated andoptionally purified. A mixture of a compound of Formula 3 is combinedwith a halogenating agent (such as oxalyl chloride), an organic base(such as pyridine), in a polar organic solvent (such as DMF and/or THF).A compound of Formula 4 is then added to give the product, a compound ofFormula 5, which is isolated and optionally purified. A compound ofFormula 5 is treated with an acidic mixture (such as hydrobromic acidand acetic acid), to provide a compound of Formula 6, where X is ahalogen (such as bromide), where the product, a compound of Formula 7,is isolated and optionally purified. A mixture of a compound of Formula6 is combined with a compound of Formula 7, where L is a leaving group(such as chloride) and Q is a substitutent group (such as carbonyl orSO₂), and an organic base (such a pyridine) to give the product, acompound of Formula 8, which is isolated and optionally purified.

wherein C, D, R₇, R₈, R₉, R₁₀ and W are as defined above for FormulaIII.

Referring to Reaction Scheme 2, Step 1B, a mixture of a compound ofFormula 1 is combined with a compound of Formula 7, where L is a leavinggroup (such as chloride) and Q is a substitutent group (such as carbonylor SO₂), and an organic base (such a pyridine) to give the product, acompound of Formula 9, which is isolated and optionally purified. Amixture of a compound of Formula 9 is combined with a halogenating agent(such as oxalyl chloride), an organic base (such as pyridine), in apolar organic solvent (such as DMF and/or THF). A compound of Formula 4is then added to give the product, a compound of Formula 8, which isisolated and optionally purified.

Referring to Reaction Scheme 4, Step 1, the alcohol of alcohol 10, isreacted with thioacetic acid under Mitsunobu conditions to give thethioacetate 11. A mixture of the thioacetate 11 and potassium carbonateis stirred in aqueous methanol to give the thiol compound 12. Thiol 12is oxidized by hydrogen peroxide in acetic acid to give the sulfonicacid 13. The sulfonic acid 13 is treated with triphosgene and thenreacted with the amine of Compound 5 to give the sulfonamide 14. The Bocprotecting group of the carbamate 14 is removed by reacting withhydrogen chloride to form the amine 15 after aqueous base (such assodium carbonate solution) treatment. The amine 15 is reacted with2-chloro-N-(2-chloroethyl)-N-methylethanamine in the presence of a base(such as potassium carbonate) to give the product, compound III-1, whichis isolated and optionally purified.

Ketone A is converted to thioketone B using hydrogen sulfide gasfollowed by sodium borohydride reduction to the thiol C. Thiol C iscoupled with compound D in N,N-dimethylformamide. The thioether E isoxidized using m-chloroperbenzoic acid at 0° C. with stirring at 0° C.in an ice/water bath for 1 h to give compound F. Afterwards ester F ishydrolyzed with sodium hydroxide in ethanol at 50° C. overnight to givethe acid G. Pyridin-3-ylmethanamine is coupled to the free acid G usingEDCI and HOBT in N,N-dimethylformamide. Finally, Compound H isdeprotected using hydrogen chloride gas in dichloromethane at 0° C. togive Compound I after standard workup.

Also provided is a pharmaceutical composition comprising at least onecompound and/or pharmaceutically acceptable salt described herein and atleast one pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” refers to any and allsolvents, dispersion media, coatings, isotonic and absorption delayingagents, and the like, that are compatible with pharmaceuticaladministration. The use of such media and agents for pharmaceuticallyactive substances is well known in the art, such as, for example,aqueous solutions such as water or physiologically buffered saline orother solvents or vehicles such as glycols, glycerol, oils such as oliveoil or injectable organic esters. The compositions may also containother active compounds providing supplemental, additional, or enhancedtherapeutic functions.

A pharmaceutically acceptable carrier may contain physiologicallyacceptable agents that act, for example, to stabilize or to increase theabsorption of a compound or pharmaceutically acceptable salt thereof.Such physiologically acceptable agents include, for example,carbohydrates, such as glucose, sucrose or dextrans, antioxidants, suchas ascorbic acid or glutathione, chelating agents, low molecular weightproteins or other stabilizers or excipients. The choice of apharmaceutically acceptable carrier, including a physiologicallyacceptable agent, may depend, for example, on the route ofadministration of the composition. The pharmaceutical composition alsomay comprise a liposome or other polymer matrix, which may haveincorporated therein, for example, a compound as described herein.Liposomes, for example, which consist of phospholipids or other lipids,are nontoxic, physiologically acceptable and metabolizable carriers thatare relatively simple to make and administer.

In some embodiments, a “pharmaceutically acceptable carrier” as usedherein means a pharmaceutically acceptable material, composition, orvehicle, such as a liquid or solid filler, diluent, excipient, solvent,or encapsulating material, involved in carrying or transporting thesubject compounds from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier is typically “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not injurious to the patient. Some examples of materialsthat may serve as pharmaceutically acceptable carriers include: (1)sugars, such as lactose, glucose and sucrose; (2) starches, such as cornstarch and potato starch; (3) cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;(4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)excipients, such as cocoa butter and suppository waxes; (9) oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; (10) glycols, such as propylene glycol; (11)polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;(12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14)buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions;and (21) other non-toxic compatible substances employed inpharmaceutical formulations. See Remington: The Science and Practice ofPharmacy, 20th ed. (Alfonso R. Gennaro ed.), 2000.

In some embodiments, a pharmaceutical composition comprising at leastone compound and/or salt as described herein may be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, boluses, powders, granules, pastesfor application to the tongue); sublingually; anally, rectally, orvaginally (for example, as a pessary, cream, or foam); parenterally(including intramusclularly, intravenously, subcutaneously, orintrathecally as, for example, a sterile solution or suspension);nasally; intraperitoneally; subcutaneously; transdermally (for exampleas a patch applied to the skin); or topically (for example, as a cream,ointment or spray applied to the skin). At least one compound and/orsalt as described herein may also be formulated for inhalation.

In some embodiments, at least one compound of Formulae I, II, III, IV.V, or VI, or a pharmaceutically acceptable salt thereof, may be simplydissolved or suspended in sterile water. Details of appropriate routesof administration and compositions suitable for same can be found in,for example, U.S. Pat. Nos. 6,110,973; 5,763,493; 5,731,000; 5,541,231;5,427,798; 5,358,970; and 4,172,896, as well as in patents citedtherein.

The pharmaceutical compositions described herein may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient that canbe combined with a carrier material to produce a single dosage form willvary depending upon the subject being treated and the particular mode ofadministration. The amount of active ingredient that can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound that produces a therapeutic effect.

In some embodiments, this amount ranges from about 1 percent to about 99percent of active ingredient.

In another embodiment, this amount ranges from about 5 percent to about70 percent, and in a further embodiment from about 10 percent to about30 percent.

Methods of preparing these compositions include the step of combining atleast one compound and/or pharmaceutically acceptable salt as describedherein with at least one carrier and, optionally, one or moreexcipients.

In some embodiments, the pharmaceutical compositions are prepared byuniformly and combining at least one compound and/or pharmaceuticallyacceptable salt as described herein with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

Pharmaceutical compositions suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of at least one compoundand/or salt as described herein as an active ingredient. Thepharmaceutical compositions described herein may also be administered asa bolus, electuary, or paste.

In some embodiments, compounds and/or pharmaceutically acceptable saltsdescribed herein are mixed with one or more pharmaceutically acceptableexcipients, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

In some embodiments, the tablets, and other solid dosage formspharmaceutical compositions, such as dragees, capsules, pills andgranules, may optionally be scored or prepared with coatings and shells,such as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition in that they release theactive ingredient(s) only, preferentially, in a certain portion of thegastrointestinal tract, optionally, or in a delayed manner. Examples ofembedding compositions that may be used include polymeric substances andwaxes. The active ingredient may also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

In some embodiments, liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredient,the liquid dosage forms may contain inert diluents commonly used in theart, such as, for example, water or other solvents, solubilizing agentsand emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, oils, cottonseed, groundnut, corn, germ,olive, castor oils, sesame oils, glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

In some embodiments, the emulsifiers are chosen from cottonseed,groundnut, corn, germ, olive, castor, and sesame oils.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Pharmaceutical compositions as described herein for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more compounds or salts as described hereinwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Alternatively or additionally, pharmaceutical compositions describedherein may be formulated for delivery via a catheter, stent, wire, orother intraluminal device. Delivery via such devices may be especiallyuseful for delivery to the bladder, urethra, ureter, rectum, orintestine.

Formulations suitable for vaginal administration also include pessaries,tampons, creams, gels, pastes, foams, or spray formulations containingsuch carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches, and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams, and gels may comprise excipients, such asanimal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to a compound as describedherein, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates, and polyamide powder, or mixtures of thesesubstances. Sprays may additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery to the body. Such dosage forms may be made by dissolving ordispersing the compound in the proper medium. Absorption enhancers mayalso be used to increase the flux across the skin. The rate of such fluxmay be controlled by either providing a rate controlling membrane ordispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions, and thelike, may also comprise at least one of the compounds or salts asdescribed herein.

In some embodiments, pharmaceutical compositions as described hereinsuitable for parenteral administration comprise at least one compound ofFormula I, or a pharmaceutically acceptable salt thereof, in combinationwith one or more pharmaceutically acceptable sterile isotonic aqueous ornonaqueous solutions, dispersions, suspensions, or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions include water, ethanol,polyols (such as glycerol, propylene glycol, polyethylene glycol, andthe like), and suitable mixtures thereof, vegetable oils, such as oliveoil, and injectable organic esters, such as ethyl oleate. Properfluidity may be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, chelators and the like.

In some embodiments, isotonic agents, such as sugars, sodium chloride,and the like may be included into the compositions. In addition,prolonged absorption of the injectable pharmaceutical form may bebrought about by the inclusion of agents that delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it may beadvantageous to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsuled matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs. A variety of biocompatible polymers (including hydrogels),including both biodegradable and non-degradable polymers, may be used toform an implant for the sustained release of a compound at a particulartarget site.

As further detailed below, the pharmaceutical compositions describedherein may also comprise, or may be used in combination with, one ormore known cytotoxic, vascular targeting agents or chemotherapeuticagents including, but not limited to, Xeloda™ (capecitabine),Paclitaxel™, FUDR (fluorouridine) Fludara™ (fludarabine phosphate),Gemzar™ (gemcitabine), methotrexate, cisplatin, carboplatin, adriamycin,avastin, tarceva, taxol, tamoxifen, Femora, temezolamide,cyclophosphamide, Erbitux, and Sutent.

In some embodiments, when pharmaceutically acceptable compositions arefor human administration, the aqueous solution is pyrogen free, orsubstantially pyrogen free. The excipients may be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition may be indosage unit form such as tablet, capsule, sprinkle capsule, granule,powder, syrup, suppository, injection or the like. The composition mayalso be present in a transdermal delivery system, e.g., a skin patch.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of a compound of Formula I, or apharmaceutically acceptable salt thereof, that are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use, as well as the zwitterionic forms,where possible, of the compounds and pharmaceutically acceptable saltsdescribed herein. A discussion is provided in Higuchi et al., “Prodrugsas Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche,E. B., ed. Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions.

Compounds included in the present compositions that are basic in natureare capable of forming a wide variety of salts with various inorganicand organic acids. The acids that may be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsare those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoricacid, as well as organic acids such as para-toluenesulfonic,methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic,citric, benzoic and acetic acid, and related inorganic and organicacids. Such pharmaceutically acceptable salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, maleate, tartrate,methanesulfonate, propanesulfonates, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, hippurate, gluconate, lactobionate,and the like salts.

In some embodiments, pharmaceutically acceptable acid addition saltsinclude those formed with mineral acids such as hydrochloric acid andhydrobromic acid, and those formed with organic acids such as fumaricacid and maleic acid.

Compounds included in the present compositions, that are acidic innature may react with any number of inorganic and organic bases to formpharmaceutically acceptable base salts. Bases may include, for example,the mineral bases, such as NaOH and KOH, but one of skill in the artwould appreciate that other bases may also be used. See Ando et al.,Remington: The Science and Practice of Pharmacy, 20th ed. 700-720(Alfonso R. Gennaro ed.), 2000.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

In some embodiments, the pharmaceutically acceptable addition salts ofthe compounds described herein may also exist as various solvates, suchas, for example, with water, methanol, ethanol, dimethylformamide, andthe like. Mixtures of such solvates may also be prepared. The source ofsuch solvate may be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent.

Methods of Using the Heteroaryl Alkylbenzamides

In some embodiments, the compounds and pharmaceutically acceptable saltsthereof described herein target cells which express HIF-1α and/orHIF-2α. In some embodiments, the compounds and pharmaceuticallyacceptable salts thereof described herein target cells which expressHIF-1α. In some embodiments, the compounds and pharmaceuticallyacceptable salts thereof described herein target cells which expressHIF-2α. In some embodiments, the compounds and pharmaceuticallyacceptable salts thereof described herein target cells which expressHIF-1α and/or HIF-2α.

In some embodiments, the compounds and pharmaceutically acceptable saltsthereof described herein target cells which do not have functional VHL.

In some embodiments, the compounds and pharmaceutically acceptable saltsdescribed herein may be used to treat cells, and more particularly,cancerous cells, expressing HIF-1α and/or HIF-2α. In some embodiments,the compounds and pharmaceutically acceptable salts described herein maybe used to treat cells, and more particularly, cancerous cells,expressing HIF-1α. In some embodiments, the compounds andpharmaceutically acceptable salts described herein may be used to treatcells, and more particularly, cancerous cells, expressing HIF-2α. Insome embodiments, the compounds and pharmaceutically acceptable saltsdescribed herein may be used to treat cells, and more particularly,cancerous cells, expressing HIF-1α and/or HIF-2α.

In some embodiments, the compounds and pharmaceutically acceptable saltsthereof interfere with glycolysis.

In certain embodiments, the disease treated or prevented is cancer.

In some embodiments, the compounds and pharmaceutically acceptable saltsdescribed herein may be used to treat a disease mediated by defectivepVHL protein, such as Von Hippel-Lindau disease (which may also bereferred to as angiomatosis retinae, angiophakomatosis retinae etcerebelli, familial cerebello-retinal angiomatosis, cerebelloretinalhemangioblastomatosis, Hippel Disease, Hippel-Lindau syndrome, HLS, VHL,Lindau disease or retinocerebellar angiomatosis). In some embodiments,the compounds and pharmaceutically acceptable salts described herein maybe used to treat a variety of malignant and/or benign tumors of the eye,brain, spinal cord, kidney, pancreas, and/or adrenal glands whereinindividuals suffering from VHL may be disposed to such tumors. In someembodiments, the compounds and pharmaceutically acceptable saltsdescribed herein may be used to treat a disease mediated by defectivepVHL protein, such as ngiomatosis, hemangioblastomas, pheochromocytoma,renal cell carcinoma, pancreatic cysts and café au lait spots.

Also provided is a method for treating a disease mediated by defectivepVHL protein, comprising administering to a subject at least onecompound of Formula I, or a pharmaceutically acceptable salt thereof,that is specifically cytotoxic to cells that have elevated HIF levelsdue to their increased rate and dependence on glucose uptake andglycolysis. In some embodiments, at least one compound of Formula Iselectively disrupts glucose uptake and utilization in the subject. Insome embodiments, at least one compound of Formula I, or apharmaceutically acceptable salt thereof, inhibits HIF-mediatedinduction of PDK1.

Also provided is a method of targeting cells which have defective pVHLprotein. In some embodiments, the cells are contacted with at least onecompound of Formula I, or a pharmaceutically acceptable salt thereof,that selectively disrupts glucose uptake and utilization in the cells.In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, inhibits HIF-mediated induction of PDK1.

Also provided is a method for selectively killing cells which havedefective pVHL protein. In some embodiments, the cells are contactedwith at least one compound of Formula I, or a pharmaceuticallyacceptable salt thereof, that selectively disrupts glucose uptake andutilization in the cells. In some embodiments, at least one compound ofFormula I, or a pharmaceutically acceptable salt thereof, inhibitsHIF-mediated induction of PDK1.

Also provided is a method for treating a disease mediated by HIF-1αand/or HIF-2α comprising administering to a subject at least onecompound of Formula I, or a pharmaceutically acceptable salt thereof,that is specifically cytotoxic to cells that have elevated HIF levelsdue to their increased rate and dependence on glucose uptake andglycolysis. In some embodiments, at least one compound of Formula I, II,III, IV, V, or VI, or a pharmaceutically acceptable salt thereof,selectively disrupts glucose uptake and utilization in the subject. Insome embodiments, at least one compound of Formula I, II, III, IV, V, orVI, or a pharmaceutically acceptable salt thereof, inhibits HIF-mediatedinduction of PDK1.

Also provided is a method for treating a disease mediated by cellscomprising genetic or epigenetic alterations that make them highlydependent on aerobic glycolysis for energy production, comprisingadministering to a subject at least one compound of Formula I, II, III,IV, V, or VI, or a pharmaceutically acceptable salt thereof, that isspecifically cytotoxic to cells comprising genetic or epigeneticalterations that make them highly dependent on aerobic glycolysis forenergy production.

Also provided is a method for selectively killing cells comprisinggenetic or epigenetic alterations that make them highly dependent onaerobic glycolysis for energy production, comprising administering tothe cells at least one compound of Formula I, II, III, IV, V, or VI, ora pharmaceutically acceptable salt thereof, that is specificallycytotoxic to cells comprising genetic or epigenetic alterations thatmake them highly dependent on aerobic glycolysis for energy production.In some embodiments, at least one compound of Formula I, II, III, IV, V,or VI, or a pharmaceutically acceptable salt thereof, selectivelydisrupts glucose uptake and utilization in cells comprising genetic orepigenetic alterations that make them highly dependent on aerobicglycolysis for energy production.

Also provided is a method for treating a disease mediated by GLUT1comprising administering to a subject in need thereof at least onecompound of Formula III, III, IV, V, or VI, or a pharmaceuticallyacceptable salt thereof. Also provided is a method for treating adisease mediated by GLUT1, comprising administering to a subject atleast one compound of Formula I, II, III, IV, V, or VI, or apharmaceutically acceptable salt thereof, that is specifically cytotoxicto cells that have elevated GLUT 1 levels due to their increased rateand dependence on glucose uptake and glycolysis. In some embodiments, atleast one compound of Formula I, II, III, IV, V, or VI, or apharmaceutically acceptable salt thereof, selectively disrupts glucoseuptake and utilization in the subject. In some embodiments, at least onecompound of Formula I II, III, IV, V, or VI, or a pharmaceuticallyacceptable salt thereof, inhibits glucose transport by GLUT1.

Also provided is a method of identifying a compound as a candidatecancer therapy, comprising exposing a first population of cells thathave elevated expression of GLUT1 but not GLUT2 to a test compound andassaying cytotoxicity of the test compound, exposing a second populationof cells that have elevated expression of GLUT2 but not GLUT1 to thetest compound and assaying cytotoxicity of the test compound, andidentifying the test compound as a candidate cancer therapy if the testcompound induces significantly higher cytotoxicity in the firstpopulation of cells than in the second population of cells. Alsoprovided is at least one compound, or a pharmaceutically acceptable saltthereof, identified by such method.

The subject receiving treatment may be any mammal in need of suchtreatment. Such mammals include, e.g., humans, ovines, bovines, equines,porcines, canines, felines, non-human primate, mice, and rats. In someembodiments, the subject is a human. In some embodiments, the subject isa non-human mammal.

“Therapeutically-effective amount” refers to the concentration of acompound that is sufficient to elicit the desired therapeutic effect(e.g., treatment or prevention of a disease). It is generally understoodthat the effective amount of the compound will vary according to theweight, gender, age, and medical history of the subject. Other factorsthat influence the effective amount may include, but are not limited to,the severity of the patient's condition, the disorder being treated, thestability of the compound, and, if desired, another type of therapeuticagent being administered with the compounds and pharmaceuticallyacceptable salts described herein. A larger total dose may be deliveredby multiple administrations of the agent. Methods to determine efficacyand dosage are known to those skilled in the art. See, e.g., Roden,Harrison's Principles of Internal Medicine, Ch. 3, McGraw-Hill, 2004.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions comprising at least one compound or pharmaceutically activesalt as described herein may be varied so as to obtain an amount of theactive ingredient that is effective to achieve the desired therapeuticresponse for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds described herein employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of at least one compound of FormulaIII, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof,will be that amount of the compound that is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described herein.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six, or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

In some embodiments, the active compound may be administered two orthree times daily. In another embodiment, the active compound isadministered once daily.

The optimal frequency of administration and effective dosage will varyfrom one individual to another and will depend upon the particulardisease being treated and may be determined by one skilled in the art.

In some embodiments, effective dosages of at least one compound ofFormula III, III, IV, V, or VI, or a pharmaceutically acceptable saltthereof, may range from as low as about 1 mg per day to as high as about1000 mg per day, including all intermediate dosages there between.

In another embodiment, effective dosages may range from about 10 mg perday to about 100 mg per day, including all intermediate dosages therebetween. The compositions may be administered in a single dosage, or inmultiple, divided dosages.

As described herein, at least one compound of Formula I, II, III, IV, V,or VI, may be used for treating or preventing cancer. In someembodiments, such methods may, further comprise administration of achemotherapeutic agent.

Chemotherapeutic agents that may be coadministered with compounds andpharmaceutical compositions of Formula I, II, III, IV, V, or VI, mayinclude: alemtuzumab, aminoglutethimide, amsacrine, anastrozole,asparaginase, Bacillus Calmette-Guérin, bevacizumab, bicalutamide,bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine,carboplatin, carmustine, CeaVac, cetuximab, chlorambucil, cisplatin,cladribine, clodronate, colchicine, cyclophosphamide, cyproterone,cytarabine, dacarbazine, daclizumab, dactinomycin, daunorubicin,dienestrol, diethylstilbestrol, docetaxel, doxorubicin, edrecolomab,epirubicin, epratuzumab, erlotinib, estradiol, estramustine, etoposide,exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil,fluoxymesterone, flutamide, gemcitabine, gemtuzumab, genistein,goserelin, huJ591, hydroxyurea, ibritumomab, idarubicin, ifosfamide,IGN-101, imatinib, interferon, interleukin-2, irinotecan, ironotecan,letrozole, leucovorin, leuprolide, levamisole, lintuzumab, lomustine,MDX-210, mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone,mitumomab, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel,pamidronate, pentostatin, pertuzumab, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, sorafinib, streptozocin,sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide,testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride,topotecan, tositumomab, trastuzumab, tretinoin, vatalanib, vinblastine,vincristine, vindesine, and vinorelbine.

Other useful chemotherapeutic agents for combination with the compoundsas described herein include MDX-010; MAb, AME; ABX-EGF; EMD 72 000;apolizumab; labetuzumab; ior-t1; MDX-220; MRA; H-11 scFv; Oregovomab;huJ591 MAb, BZL; visilizumab; TriGem; TriAb; R3; MT-201; G-250,unconjugated; ACA-125; Onyvax-105; CDP-860; BrevaRex MAb; AR54;IMC-1C11; GlioMAb-H; ING-1; Anti-LCG MAbs; MT-103; KSB-303; Therex;KW-2871; Anti-HMI.24; Anti-PTHrP; 2C4 antibody; SGN-30; TRAIL-RIMAb,CAT; Prostate cancer antibody; H22xKi-4; ABX-MA1; Imuteran; andMonopharm-C.

These chemotherapeutic agents may be categorized by their mechanism ofaction into, for example, the following groups:anti-metabolites/anti-cancer agents, such as pyrimidine analogs (e.g.,5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine)and purine analogs, folate antagonists and related inhibitors (e.g.,mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine(cladribine)); antiproliferative/antimitotic agents including naturalproducts such as vinca alkaloids (e.g., vinblastine, vincristine, andvinorelbine), microtubule disruptors such as taxane (paclitaxel,docetaxel), vincristin, vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (teniposide), DNA damaging agents(e.g., actinomycin, amsacrine, anthracyclines, bleomycin, busulfan,camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide,cytoxan, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin,hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorethamine, mitomycin, mitoxantrone, nitrosourea, paclitaxel,plicamycin, procarbazine, teniposide, triethylenethiophosphoramide andetoposide (VP16)); antibiotics such as dactinomycin (actinomycin D),daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines,mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin;enzymes (e.g., L-asparaginase, which systemically metabolizesL-asparagine and deprives cells which do not have the capacity tosynthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (e.g., mechlorethamine, cyclophosphamide and analogs,melphalan, chlorambucil), ethylenimines and methylmelamines (e.g.,hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,nitrosoureas (e.g., carmustine (BCNU) and analogs, streptozocin),trazenes—dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (e.g., methotrexate);platinum coordination complexes (e.g., cisplatin, carboplatin),procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones,hormone analogs (e.g., estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (e.g., letrozole, anastrozole);anticoagulants (e.g., heparin, synthetic heparin salts and otherinhibitors of thrombin); fibrinolytic agents (such as tissue plasminogenactivator, streptokinase and urokinase), aspirin, COX-2 inhibitors,dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents;antisecretory agents (e.g., breveldin); immunosuppressives (e.g.,cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine,mycophenolate mofetil); anti-angiogenic compounds (e.g., TNP-470,genistein) and growth factor inhibitors (e.g., vascular endothelialgrowth factor (VEGF) inhibitors, fibroblast growth factor (FGF)inhibitors, epidermal growth factor (EGF) inhibitors); angiotensinreceptor blocker; nitric oxide donors; anti-sense oligonucleotides;antibodies (e.g., trastuzumab and others listed above); cell cycleinhibitors and differentiation inducers (e.g., tretinoin); mTORinhibitors, topoisomerase inhibitors (e.g., doxorubicin (adriamycin),amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide,epirubicin, etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone,topotecan, irinotecan), corticosteroids (e.g., cortisone, dexamethasone,hydrocortisone, methylpednisolone, prednisone, and prenisolone); growthfactor signal transduction kinase inhibitors; mitochondrial dysfunctioninducers and caspase activators; chromatin disruptors.

In some embodiments, pharmaceutical compositions comprising at least onecompound of Formula I, II, III, IV, V, or VI, may be coadministered withchemotherapeutic agents either singly or in combination.

Combination therapies comprising at least one compound of Formula I, II,III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, and aconventional chemotherapeutic agent may be advantageous over combinationtherapies known in the art because the combination allows theconventional chemotherapeutic agent to exert greater effect at lowerdosage. In some embodiments, the effective dose (ED₅₀) for achemotherapeutic agent, or combination of conventional chemotherapeuticagents, when used in combination with a compound of Formula I, II, III,IV, V, or VI, or a pharmaceutically acceptable salt thereof as describedherein is at least 2 fold less than the ED₅₀ for the chemotherapeuticagent alone. In another embodiment, the ED₅₀ is about 5-fold less, about10-fold less, and further about 25-fold less. Conversely, thetherapeutic index (TI) for such chemotherapeutic agent or combination ofsuch chemotherapeutic agent when used in combination with a compound orpharmaceutically acceptable salt described herein may be at least 2-foldgreater than the TI for conventional chemotherapeutic regimen alone. Inanother embodiment, the TI is about 5-fold greater, about 10-foldgreater, and further about 25-fold greater.

In some embodiments, the compounds and pharmaceutically acceptable saltsthereof described herein may be administered in combination withradiation therapy.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Analyses were carried out in the Campbell Microanalytical Laboratory,University of Otago, Dunedin, NZ. Melting points were determined on anElectrothermal 2300 Melting Point Apparatus. NMR spectra were obtainedon a Bruker Avance 400 spectrometer at 400 MHz for ¹H and 100 MHz for¹³C spectra. Spectra were obtained in [(CD₃)₂SO] unless otherwisespecified, and were referenced to Me₄Si. Chemical shifts and couplingconstants were recorded in units of ppm and Hz, respectively.Assignments were determined using COSY, HSQC, and HMBC two-dimensionalexperiments. Low resolution mass spectra were gathered by directinjection of methanolic solutions into a Surveyor MSQ mass spectrometerusing an atmospheric pressure chemical ionization (APCI) mode with acorona voltage of 50 V and a source temperature of 400° C. Solutions inorganic solvents were dried with anhydrous MgSO₄. Solvents wereevaporated under reduced pressure on a rotary evaporator. Thin-layerchromatography was carried out on aluminium-backed silica gel plates(Merck 60 F₂₅₄) with visualization of components by UV light (254 nm) orexposure to I₂. Column chromatography was carried out on silica gel(Merck 230-400 mesh). DCM refers to dichloromethane; DIEA refers todiisopropylethylamine; DME refers to dimethoxyethane, DMF refers to dryN,N-dimethylformamide; ether refers to diethyl ether; EtOAc refers toethyl acetate; EtOH refers to ethanol; HBTU refers toO-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate; MeOHrefers to methanol; pet. ether refers to petroleum ether, boiling range40-60° C.; THF refers to tetrahydrofuran dried over sodium benzophenoneketyl.

Method A

A mixture of chloride (1.0 mmol) and sodium arylsulfinate (1.1 mmol) indry DMF (20 mL) was stirred at 70° C. for 3 h. The solvent wasevaporated and the residue was suspended in EtOAc (100 mL) and washedwith water (2×20 mL), washed with brine (20 mL) and dried. The solventwas evaporated and the residue purified by column chromatography to givebenzoate.

Method B

A mixture of chloride (1.0 mmol), arylthiol (1.1 mmol) and K₂CO₃ (1.1mmol) in dry DMF (20 mL) was stirred at 70° C. for 16 h. The mixture wascooled to 5° C. and mCPBA (2.5 mmol) was added and the mixture stirredat 5° C. for 1 h. The mixture was poured into water (100 mL) and stirredfor 30 min. The precipitate was filtered, washed with water and thenpartitioned between EtOAc (100 mL) and dilute aqueous NH₃ (2×50 mL). Theorganic fraction was washed with water (50 mL), washed with brine (30mL) and dried. The solvent was evaporated and the residue purified bycolumn chromatography to give benzoate.

Method C

A mixture of benzoate (1.0 mmol) and 6 M HCl (10 mL) was stirred atreflux temperature for 16 h. The mixture was cooled and diluted withice/water (40 ml) and stirred for 30 min. The precipitate was filtered,washed with water (20 mL) and dried to give the acid.

Method D

A mixture of benzoate (1.0 mmol) and 2 M NaOH (10 mL) in dioxane (10 mL)was stirred at reflux temperature for 2 h. The mixture was cooled andthe organic solvent evaporated. The remaining mixture was diluted withwater (40 mL) and washed with Et₂O (10 mL). The pH of the aqueous phasewas adjusted to 2 with 6 M HCl and the mixture was stirred at 5° C. for1 h. The precipitate was filtered, washed with water (10 mL) and driedto give acid.

Method E

Oxalyl chloride (1.5 mmol) was added dropwise to a stirred suspension ofbenzoic acid (1.0 mmol) and DMF (2 drops) in dry THF (20 mL) and thesolution was stirred at 20° C. for 2 h, then at 66° C. for 1 h. Thesolution was cooled to 20° C. and the solvent was evaporated. Theresidue was dissolved in dry pyridine (10 mL) and amine (1.1 mmol) wasadded and the solution stirred at 20° C. for 16 h. The solvent wasevaporated and the residue suspended in ice/water (50 mL) for 1 h. Theprecipitate was filtered, washed with water (5 mL) and dried. The crudesolid was purified by column chromatography to give benzamide.

Example 14-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinyl)benzamide(5)

Methyl 4-(4,5-Dimethyl-3-oxido-1,3-oxazol-2-yl)benzoate (1)

HCl gas was bubbled through a solution of methyl 4-formylbenzoate (8.20g, 50.0 mmol) and 2,3-butanedione 2-oxime (5.05 g, 50 mmol) in HOAc (25mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. Themixture was diluted with Et₂O (300 mL) and the resulting precipitate wasfiltered, washed with Et₂O (50 mL) and dried in vacuo to give N-oxide 1(12.05 g, 97%) as a white powder: mp (Et₂O) 127-128° C.; ¹H NMR (CDCl₃)δ 8.44 (br d, J=8.8 Hz, 2H, H-2, H-6), 8.23 (br d, J=8.8 Hz, 2H, H-3,H-5), 3.98 (s, 3H, OCH₃), 2.50 (s, 2H, CH₃), 2.47 (s, 3H, CH₃); MS m/z248.6 (MH⁺, 100%).

Methyl 4-[4-(Chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (2)

POCl₃ (2.23 mL, 24.3 mmol) was added dropwise to a stirred solution ofN-oxide 1 (5.0 g, 20.2 mmol) in dry DCM (100 mL) and the mixture stirredat 40° C. for 16 h. The solution was poured into a slurry of ice/1 MNaOH solution (100 mL) and the mixture stirred for 10 min. The mixturewas extracted with DCM (3×50 mL), the combined organic extract dried andthe solvent evaporated. The residue was purified by columnchromatography, eluting with 20% EtOAc/pet. ether, to give benzoate 2(4.12 g, 77%) as a white powder: mp (EtOAc) 127-128° C.; ¹H NMR (CDCl₃)δ 8.06-8.12 (m, 4H, H-2, H-3, H-5, H-6), 4.56 (s, 2H, CH₂Cl), 3.94 (s,3H, OCH₃), 2.45 (s, 3H, CH₃); MS m/z 266.6 (MH⁺, 100%). Anal. calcd forC₁₃H₁₂ClNO₃: C, 58.77; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.43; N,5.18%.

Methyl4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoate(3)

Method A.

A mixture of chloride 2 (1.54 g, 5.8 mmol) and sodium4-methylbenzenesulfinate (1.08 g, 6.1 mmol) gave benzoate 3 (1.96 g,88%) as a white powder: mp (EtOAc) 177-178° C.; ¹H NMR (CDCl₃) δ 8.08(ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-2, H-6), 7.92 (ddd, J=8.7, 2.0, 1.6 Hz,2H, H-3, H-5), 7.69 (ddd, J=8.3, 1.9, 1.7 Hz, 2H, H-2′, H-6′), 7.30 (brd, J=8.3 Hz, 2H, H-3′, H-5′), 4.29 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃),2.43 (s, 3H, CH₃), 2.31 (s, 3H, CH₃); MS m/z 386.5 (MH⁺, 100%). Anal.calcd for C₂₀H₁₉NO₅S: C, 62.32; H, 4.97; N, 3.63. Found: C, 62.59; H,4.96; N, 3.71%.

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoicAcid (4)

Method C.

Reaction of benzoate 3 (1.96 g, 5.1 mmol) and 6 M HCl (50 mL) gave acid4 (1.83 g, 97%) as a white solid: mp (H₂O) 242-245° C.; ¹H NMR δ 13.16(br s, 1H, CO₂H), 8.05 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.92(ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.67 (br d, J=8.3 Hz, 2H, H-2′,H-6′), 7.42 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 4.63 (s, 2H, CH₂SO₂), 2.40(s, 3H, CH₃), 2.13 (s, 3H, CH₃); MS m/z 372.8 (MH⁺, 100%). Anal. calcdfor C₁₉H₁₇NO₅S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.67; H, 4.57; N,3.79%.

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-5pyridinyl)benzamide (5)

Method E.

Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (207mg, 0.6 mmol) with subsequent coupling to 3-aminopyridine (58 mg, 0.6mmol) gave benzamide 5 (148 mg, 59%) as a white powder: mp (EtOAc)248-250° C.; ¹H NMR δ 10.56 (s, 1H, CONH), 8.94 (d, J=2.2 Hz, 1H, H-2′),8.33 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.20 (ddd, J=8.3, 2.5, 1.5 Hz, 1H,H-4′), 8.10 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.97 (br d, J=8.6 Hz, 2H,H-3, H-5), 7.69 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.38-7.45 (m, 3H,H-5′, H-3″, H-5″), 4.65 (s, 2H, CH₂SO₂), 2.41 (s, 3H, CH₃), 2.16 (s, 3H,CH₃); ¹³C NMR δ 165.0, 157.9, 150.1, 144.7 (2), 144.5, 142.1, 135.6,135.5, 129.7 (2), 129.3, 128.6 (2), 128.3 (2), 127.4, 126.1, 125.5 (2),123.5, 53.0, 21.1, 9.7; MS m/z 448.7 (MH⁺, 100%). Anal. calcd forC₂₄H₂₁N₃O₄S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.18; H, 4.74; N,9.39%.

Example 24-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinyl)benzamide(6)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinyl)benzamide(6)

Method E.

Reaction of oxalyl chloride (70 λL, 0.8 mmol) and benzoic acid 4 (200mg, 0.5 mmol) with subsequent coupling to 4-aminopyridine (56 mg, 0.6mmol) gave starting material (52 mg, 26%) and benzamide 6 (157 mg, 65%)as a white powder: mp (EtOAc) 229-231° C.; ¹H NMR δ 10.69 (s, 1H, CONH),8.50 (dd, J=6.3, 1.5 Hz, 2H, H-2′, H-6′), 8.10 (dd, J=8.6, 1.8 Hz, 2H,H-2, H-6), 7.97 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.80 (dd, J=6.3, 1.5Hz, 2H, H-3′, H-5′), 7.68 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.43 (br d,J=8.3 Hz, 2H, H-3″, H-5″), 4.65 (s, 2H, CH₂SO₂), 2.41 (s, 3H, CH₃), 2.16(s, 3H, CH₃); ¹³C NMR δ 165.6, 157.9, 150.3 (2), 150.1, 145.8, 144.5,135.6, 135.4, 129.7 (2), 129.5, 128.7 (2), 128.3 (2), 126.1, 125.5 (2),114.1 (2), 53.0, 21.1, 9.7; MS m/z 448.7 (MH⁺, 100%). Anal. calcd forC₂₄H₂₁N₃O₄S.¼CH₃OH: C, 63.94; H, 4.87; N, 9.23. Found: C, 63.89; H,4.86; N, 9.02%.

Example 3N-Methyl-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinyl)benzamide(7)

N-Methyl-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinyl)benzamide(7)

Method E.

Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (275mg, 0.7 mmol) with subsequent coupling to N-methyl-N-(3-pyridinyl)amine(88 mg, 0.8 mmol) gave benzamide 7 (237 mg, 69%) as a white powder: mp(MeOH) 195-197° C.; ¹H NMR δ 8.37 (d, J=2.4 Hz, 1H, H-2′), 8.35 (dd,J=4.7, 1.5 Hz, 1H, H-6′), 7.72 (ddd, J=8.2, 2.4, 1.5 Hz, 1H, H-4′), 7.67(br d, J=8.5 Hz, 2H, H-2, H-6), 7.63 (br d, J=8.2 Hz, 2H, H-2″, H-6″),7.37-7.42 (m, J=8.2 Hz, 4H, H-3, H-5, H-3″, H-5″), 7.34 (ddd, J=8.2, 4.7Hz, 1H, H-5′), 4.58 (s, 2H, CH₂SO₂), 3.42 (s, 3H, NCH₃), 2.34 (s, 3H,CH₃), 2.06 (s, 3H, CH₃); ¹³C NMR δ 168.8, 157.8, 149.8, 148.1, 147.3,144.4, 140.7, 137.4, 135.5, 134.2, 129.6 (2), 129.0 (2), 128.2 (2),127.2, 125.9, 125.0 (2), 123.8, 52.9, 37.6, 21.0, 9.6; MS m/z 462.6(MH⁺, 100%). Anal. calcd for C₂₅H₂₃N₃O₄S: C, 65.06; H, 5.02; N, 9.10.Found: C, 64.90; H, 4.92; N, 8.83%.

Example 44-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyridinylmethyl)benzamide(8)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyridinylmethyl)benzamide(8)

Method E.

Reaction of oxalyl chloride (75 λL, 0.9 mmol) and benzoic acid 4 (215mg, 0.6 mmol) with subsequent coupling to 2-pyridinylmethylamine (68 λL,0.6 mmol) gave benzamide 8 (221 mg, 83%) as a white powder: mp (EtOAc)154-155° C.; ¹H NMR δ 9.21 (t, J=6.0 Hz, 1H, CONH), 8.52 (dd, J=4.8, 1.5Hz, 1H, H-6′), 8.04 (d, J=8.6 Hz, 2H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2H,H-3, H-5), 7.77 (dt, J=7.8, 1.8 Hz, 1H, H-4′), 7.67 (d, J=8.3 Hz, 2H,H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.35 (d, J=7.8 Hz, 1H,H-3′), 7.27 (dd, J=7.7, 4.8 Hz, 1H, H-5′), 4.63 (s, 2H, CH₂SO₂), 4.59(d, J=6.0 Hz, 2H, CH₂N), 2.41 (s, 3H, CH₃), 2.14 (s, 3H, CH₃); ¹³C NMR δ165.6, 158.6, 158.0, 149.9, 148.8, 144.5, 136.7, 135.6, 135.5, 129.6(2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 122.1, 121.0, 53.0,44.8, 21.0, 9.7; MS m/z 462.6 (MH⁺, 100%). Anal. calcd for C₂₅H₂₃N₃O₄S:C, 65.06; H, 5.02; N, 9.10. Found: C, 65.03; H, 5.00; N, 9.11%.

Example 54-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(9)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(9)

Method E.

Reaction of oxalyl chloride (195 λL, 2.2 mmol) and benzoic acid 4 (415mg, 1.1 mmol) and subsequent coupling to 3-pyridinylmethylamine (125 λL,1.2 mmol) gave benzamide 9 (406 mg, 79%) as a white powder: mp (EtOAc)190-191° C.; ¹H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.7 Hz,1H, H-2′), 8.47 (dd, J=4.8, 1.5 Hz, 1H, H-6′), 8.00 (d, J=8.5 Hz, 2H,H-2, H-6), 7.90 (d, J=8.4 Hz, 2H, H-3, H-5), 7.74 (dt, J=7.8, 1.8 Hz,1H, H-4′), 7.67 (d, J=8.2 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.2 Hz, 2H,H-3″, H-5″), 7.36 (dd, J=7.8, 4.8 Hz, 1H, H-5′), 4.63 (s, 2H, CH₂SO₂),4.51 (d, J=5.8 Hz, 2H, CH₂N), 2.40 (s, 3H, CH₃), 2.13 (s, 3H, CH₃); ¹³CNMR δ 165.5, 158.0, 149.9, 148.9, 148.1, 144.5, 135.6, 135.4, 135.2,134.9, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 123.5,53.0, 40.6, 21.0, 9.7; MS m/z 462.7 (MH⁺, 100%). Anal. calcd forC₂₅H₂₃N₃O₄S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.79; H, 5.03; N,9.15%.

Example 64-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinylmethyl)benzamide(10)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(4-pyridinylmethyl)benzamide(10)

Method E.

Reaction of oxalyl chloride (178 λL, 2.0 mmol) and benzoic acid 4 (379mg, 1.0 mmol) with subsequent coupling to 4-pyridinylmethylamine (114λL, 1.1 mmol) gave benzamide 10 (336 mg, 71%) as a white powder: mp(EtOAc) 169-172° C.; ¹H NMR δ 9.24 (t, J=5.9 Hz, 1H, CONH), 8.50 (dd,J=4.4, 1.6 Hz, 2H, H-2′, H-6′), 8.03 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6),7.92 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2″,H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.32 (dd, J=4.4, 1.6 Hz, 2H,H-3′, H-5′), 4.63 (s, 2H, CH₂SO₂), 4.51 (d, J=5.9 Hz, 2H, CH₂N), 2.41(s, 3H, CH₃), 2.14 (s, 3H, CH₃); ¹³C NMR δ 165.7, 158.0, 150.0, 148.9(2), 148.4, 144.5, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2),126.0, 125.5 (2), 122.2 (2), 53.0, 41.8, 21.1, 9.7; MS m/z 462.8 (MH⁺,100%). Anal. calcd for C₂₅H₂₃N₃O₄S: C, 65.06; H, 5.02; N, 9.10. Found:C, 65.10; H, 4.96; N, 9.10%.

Example 7N-Methyl-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(11)

N-Methyl-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(11)

Method E.

Reaction of oxalyl chloride (132 λL, 1.5 mmol) and benzoic acid 4 (376mg, 1.0 mmol) with subsequent coupling toN-methyl-N-(3-pyridinylmethyl)amine (51 mg, 1.1 mmol) gave benzamide 11(322 mg, 67%) as a white powder: mp (EtOAc) 77-80° C.; ¹H NMR δ 8.59 (brs, 1H, H-2′), 8.52 (br d, J=4.5 Hz, 1H, H-6′), 7.87 (br d, J=7.6 Hz, 2H,H-2, H-6), 7.77 (br s, 1H, H-4′), 7.66 (br d, J=8.2 Hz, 2H, H-2″, H-6″),7.58 (br s, 2H, H-3, H-5), 7.38-7.44 (m, 3H, H-5′, H-3″, H-5″), 4.71 (brs, 2H, CH₂N), 4.62 (s, 2H, CH₂SO₂), 2.90 (s, 3H, NCH₃), 2.39 (s, 3H,CH₃), 2.11 (s, 3H, CH₃); ¹³C NMR δ 169.7, 158.0, 149.7, 149.1, 148.6,144.5, 137.6, 135.6, 135.5, 132.9, 129.6 (2), 128.2 (2), 127.8 (2),127.4, 125.9, 125.5 (2), 123.7, 52.9, 47.8, 37.0, 21.0, 9.6; MS m/z476.7 (MH⁺, 100%). Anal. calcd for C₂₆H₂₅N₃O₄S: C, 65.67; H, 5.30; N,8.84. Found: C, 65.46; H, 5.37; N, 8.67%.

Example 84-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-[2-(3-pyridinyl)ethyl]benzamide(12)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-[2-(3-pyridinyl)ethyl]benzamide(12)

Method E.

Reaction of oxalyl chloride (71 λL, 0.82 mmol) and benzoic acid 4 (202mg, 0.54 mmol) with subsequent reaction with 2-(3-pyridinyl)ethylamine(71 λL, 0.59 mmol) gave benzamide 12 (208 mg, 81%) as a white powder: mp(EtOAc) 207-208° C.; ¹H NMR δ 8.68 (t, J=5.6 Hz, 1H, CONH), 8.46 (d,J=1.7 Hz, 1H, H-2′), 8.41 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 7.93 (dd,J=8.6, 2.0 Hz, 2H, H-2, H-6), 7.87 (dd, J=8.6, 2.0 Hz, 2H, H-3, H-5),7.65-7.69 (m, 3H, H-4′, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″),7.31 (ddd, J=7.8, 4.7, 0.7 Hz, 1H, H-5′), 4.62 (s, 2H, CH₂SO₂), 3.54(dt, J=7.0, 5.8 Hz, 2H, CH₂N), 2.89 (t, J=7.1 Hz, 2H, CH₂), 2.40 (s, 3H,CH₃), 2.13 (s, 3H, CH₃); ¹³C NMR δ 165.4, 158.0, 149.9, 149.8, 147.4,144.5, 136.2, 135.8, 135.6, 134.9, 129.6 (2), 128.7, 128.3 (2), 127.9(2), 126.0, 125.4 (2), 123.4, 53.0, 40.4, 32.0, 21.0, 9.7; MS m/z 476.6(MH⁺, 100%). Anal. calcd for C₂₆H₂₅N₃O₄S: C, 65.67; H, 5.30; N, 8.84.Found: C, 65.53; H, 5.18; N, 8.75%.

Example 94-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyrazinylmethyl)benzamide(13)

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(2-pyrazinylmethyl)benzamide(13)

Method E.

Reaction of oxalyl chloride (74 λL, 0.8 mmol) and benzoic acid 4 (209mg, 0.6 mmol) with subsequent coupling to 2-pyrazinylmethylamine (90 mg,0.6 mmol) gave benzamide 13 (192 mg, 74%) as a white powder: mp (EtOAc)204-206° C.; ¹H NMR δ 9.30 (t, J=5.8 Hz, 1H, CONH), 8.66 (d, J=1.5 Hz,1H, H-3′), 8.59 (dd, J=2.6, 1.5 Hz, 1H, H-5′), 8.54 (d, J=2.6 Hz, 1H,H-6′), 8.02 (d, J=8.6 Hz, 2H, H-2, H-6), 7.90 (d, J=8.6 Hz, 2H, H-3,H-5), 7.67 (d, J=8.3 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″,H-5″), 4.62-4.66 (m, 4H, CH₂SO₂, CH₂N), 2.41 (s, 3H, CH₃), 2.14 (s, 3H,CH₃); ¹³C NMR δ 165.7, 158.0, 154.1, 149.9, 144.5, 143.9, 143.5, 143.2,135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.4 (2),53.0, 42.9, 21.0, 9.7; MS m/z 433.6 (MH⁺, 100%). Anal. calcd forC₂₄H₂₂N₄O₄S: C, 62.32; H, 4.79; N, 12.11. Found: C, 62.36; H, 4.67; N,12.09%.

Example 10N-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide(14)

N-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide(14)

Method E.

Reaction of oxalyl chloride (75 λL, 0.86 mmol) and benzoic acid 4 (212mg, 0.57 mmol) with subsequent coupling to(1-methyl-1H-imidazol-2-yl)methylamine (70 mg, 0.63 mmol) gave benzamide14 (185 mg, 70%) as a white powder: mp (EtOAc) 190-192° C.; ¹H NMR δ9.05 (t, J=5.5 Hz, 1H, CONH), 8.00 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6),7.87 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2′,H-6′), 7.42 (d, J=8.3 Hz, 2H, H-3′, H-5′), 7.08 (d, J=1.1 Hz, 1H, H-5″),6.80 (d, J=1.1 Hz, 1H, H-4″), 4.62 (s, 2H, CH₂SO₂), 4.54 (d, J=5.5 Hz,2H, CH₂N), 3.66 (s, 3H, NCH₃), 2.40 (s, 3H, CH₃), 2.13 (s, 3H, CH₃); ¹³CNMR δ 165.2, 158.0, 149.9, 144.5 (2), 135.6, 135.3, 129.6 (2), 128.8,128.3 (2), 128.2 (2), 126.4, 126.0, 125.3 (2), 121.8, 53.0, 35.5, 32.4,21.0, 9.6; MS m/z 462.5 (MH⁺, 100%). Anal. calcd for C₂₄H₂₄N₄O₄S: C,62.05; H, 5.21; N, 12.06. Found: C, 61.76; H, 5.09; N, 11.76%.

Example 11N-[(1-Methyl-1H-imidazol-5-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide(15)

N-[(1-Methyl-1H-imidazol-5-yl)methyl]-4-(5-methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzamide(15)

Method E.

Reaction of oxalyl chloride (111 λL, 1.27 mmol) and benzoic acid 4 (318mg, 0.85 mmol) with subsequent coupling to(1-methyl-1H-imidazol-5-yl)methylamine (104 mg, 0.94 mmol) gavebenzamide 15 (325 mg, 82%) as a white powder: mp (EtOAc) 240-242° C.; ¹HNMR δ 8.93 (t, J=5.3 Hz, 1H, CONH), 7.97 (br d, J=8.5 Hz, 2H, H-2, H-6),7.87 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.67 (br d, J=8.3 Hz, 2H, H-2′,H-6′), 7.54 (s, 1H, H-2″), 7.42 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 6.84(s, 1H, H-4″), 4.62 (s, 2H, CH₂SO₂), 4.48 (d, J=5.3 Hz, 2H, CH₂N), 3.62(s, 3H, NCH₃), 2.40 (s, 3H, CH₃), 2.13 (s, 3H, CH₃); ¹³C NMR δ 165.1,157.9, 149.8, 144.4, 138.1, 135.5, 135.4, 129.5 (2), 128.7, 128.6, 128.1(2), 128.0 (2), 127.7, 125.9, 125.2 (2), 52.8, 32.5, 30.9, 20.9, 9.5; MSm/z 465.5 (MH⁺, 100%). Anal. calcd for C₂₄H₂₄N₄O₄S: C, 62.05; H, 5.21;N, 12.06. Found: C, 62.42; H, 5.24; N, 12.12%.

Example 124-[5-Methyl-4-[(phenylsulfonyl)methyl]-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(18)

Methyl 4-[5-methyl-4-[(phenylsulfonyl)methyl]-1,3-oxazol-2-yl]benzoate(16)

Method A.

Reaction of chloride 2 (267 mg, 1.0 mmol) and sodium benzenesulfinate(173 mg, 1.1 mmol) gave benzoate 16 (311 mg, 84%) as a white powder: mp(EtOAc) 159-161° C.; ¹H NMR (CDCl₃) δ 8.07 (ddd, J=8.7, 1.9, 1.5 Hz, 2H,H-2, H-6), 7.91 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.82 (ddd,J=8.2, 2.0, 1.2 Hz, 2H, H-2′, H-6′), 7.64 (tt, J=7.5, 1.2 Hz, 1H, H-4′),7.52 (br dd, J=8.2, 7.5 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH₂SO₂), 3.94(s, 3H, OCH₃), 2.32 (s, 3H, CH₃); MS m/z 372.3 (MH⁺, 100%). Anal. calcdfor C₁₉H₁₇NO₅S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.75; H, 4.62; N,3.75%.

4-[5-Methyl-4-[(phenylsulfonyl)methyl]-1,3-oxazol-2-yl]benzoic Acid (17)

Method C.

Reaction of benzoate 16 (290 mg, 0.78 mmol) and 6 M HCl (5 mL) gave acid17 (278 mg, 100%) as a white solid: mp (H₂O) 284-287° C.; ¹H NMR δ 12.68(br s, 1H, CO₂H), 8.04 (br d, J=8.4 Hz, 2H, H-2, H-6), 7.90 (br d, J=8.4Hz, 2H, H-3, H-5), 7.80 (br ddd, J=8.1, 1.9, 1.2 Hz, 2H, H-2′, H-6′),7.75 (tt, J=7.5, 1.2 Hz, 1H, H-4′), 7.62 (br dd, J=8.1, 7.4 Hz, 2H,H-3′, H-5′), 4.68 (s, 2H, CH₂SO₂), 2.13 (s, 3H, CH₃); MS m/z 358.8 (MH⁺,100%).

4-[5-Methyl-4-[(phenylsulfonyl)methyl]-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(18)

Method E.

Reaction of oxalyl chloride (102 λL, 1.17 mmol) and benzoic acid 17 (280mg, 0.78 mmol) with subsequent coupling to 3-pyridinylmethylamine (87λL, 0.86 mmol) gave benzamide 18 (169 mg, 48%) as a white powder: mp(EtOAc) 196-198° C.; ¹H NMR δ 9.20 (t, J=5.9 Hz, 1H, CONH), 8.57 (br s,1H, H-2′), 8.46 (br s, 1H, H-6′), 8.00 (br dd, J=8.6, 1.8 Hz, 2H, H-2,H-6), 7.89 (br dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.80 (br d, J=8.5 Hz,2H, H-2″, H-6″), 7.71-7.76 (m, 2H, H-4′, H-4″), 7.62 (br dd, J=8.2, 7.5Hz, 2H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8 Hz, 1H, H-5′), 4.68 (s, 2H,CH₂SO₂), 4.50 (d, J=5.8 Hz, 2H, CH₂N), 2.13 (s, 3H, CH₃); ¹³C NMR δ165.4, 157.9, 149.9, 148.8, 148.0, 138.3, 135.3, 135.0, 134.8, 133.8,129.1 (2), 128.7, 128.1 (2), 128.0 (2), 125.8, 125.3 (2), 123.4, 52.7,40.4, 9.5; MS m/z 448.5 (MH⁺, 100%). Anal. calcd for C₂₄H₂₁N₃O₄S: C,64.41; H, 4.73; N, 9.39. Found: C, 64.23; H, 4.71; N, 9.37%.

Example 134-(4-{[(4-Chlorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(21)

Methyl4-(4-{[(4-Chlorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(19)

Method A.

Reaction of chloride 2 (268 mg, 1.0 mmol) and sodium4-chlorobenzenesulfinate (198 mg, 1.0 mmol) gave benzoate 19 (273 mg,67%) as a white powder: mp (EtOAc) 186-188° C.; ¹H NMR (CDCl₃) δ 8.08(ddd, J=8.7, 1.9, 1.6 Hz, 2H, H-2, H-6), 7.90 (ddd, J=8.7, 1.9, 1.6 Hz,2H, H-3, H-5), 7.74 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-2′, H-6′), 7.49(ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH₂SO₂), 3.94(s, 3H, OCH₃), 2.37 (s, 3H, CH₃); MS m/z 407.0 (MH⁺, 100%), 409.0 (MH⁺,35%). Anal. calcd for C₁₉H₁₆ClNO₅S: C, 56.23; H, 3.97; N, 3.45. Found:C, 56.11; H, 3.80; N, 3.35%.

4-(4-{[(4-Chlorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (20)

Method C.

Reaction of benzoate 19 (217 mg, 0.53 mmol) and 6 M HCl (5 mL) gave acid20 (208 mg, 100%) as a white solid: mp (H₂O) 268-271° C.; ¹H NMR[(CD₃)₂SO] δ 13.18 (br s, 1H, CO₂H), 8.04 (dd, J=8.6, 1.8 Hz, 2H, H-2,H-6), 7.90 (br dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.81 (ddd, J=8.7, 2.4,2.0 Hz, 2H, H-2′, H-6′), 7.70 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-3′, H-5′),4.74 (s, 2H, CH₂SO₂), 2.21 (s, 3H, CH₃); MS m/z 393.2 (MH⁺, 100%), 393.0(MH⁺, 35%). Anal. calcd for C₁₈H₁₄ClNO₅S: C, 55.18; H, 3.60; N, 3.57.Found: C, 55.22; H, 3.41; N, 3.47%.

4-(4-{[(4-Chlorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(21)

Method E.

Reaction of oxalyl chloride (60 λL, 0.69 mmol) and benzoic acid 20 (179mg, 0.46 mmol) with subsequent coupling to 3-pyridinylmethylamine (51λL, 0.50 mmol) gave benzamide 21 (183 mg, 85%) as a white powder: mp(EtOAc) 220-222° C.; ¹H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.56 (d,J=1.6 Hz, 1H, H-2′), 8.51 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.6Hz, 2H, H-2, H-6), 7.88 (d, J=8.6 Hz, 2H, H-3, H-5), 7.81 (ddd, J=8.7,2.4, 1.9 Hz, 2H, H-2″, H-6″), 7.74 (br dt, J=7.9, 1.8 Hz, 1H, H-4′),7.70 (ddd, J=8.7, 2.4, 1.9 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=7.9, 4.7 Hz,1H, H-5′), 4.73 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 2.21 (s,3H, CH₃); ¹³C NMR δ 165.4, 158.0, 150.0, 148.8, 148.0, 139.0, 137.3,135.4, 135.1, 134.8, 130.2 (2), 129.2 (2), 128.7, 128.0 (2), 125.6,125.3 (2), 123.4, 52.7, 40.4, 9.7; MS m/z 483.3 (MH⁺, 100%). Anal. calcdfor C₂₄H₂₀ClN₃O₄S: C, 59.81; H, 4.18; N, 8.72. Found: C, 60.12; H, 4.09;N, 8.82%.

Example 144-(4-{[(4-tert-Butylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(24)

Methyl4-(4-{[(4-tert-Butylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(22)

A solution of Na₂SO₃ (126 mg, 1.0 mmol) and Na₂CO₃ (106 mg, 1.0 mmol) inwater (2 mL) was added to a suspension of 4-tert-butylbenzenesulfonylchloride (233 mg, 1.0 mmol) in water (5 mL) and the mixture was stirredat 100° C. for 2 h. A solution of chloride 2 (268 mg, 1.0 mmol) in EtOH(5 mL) was added and the mixture stirred at 100° C. for 16 h. Themixture was cooled and diluted with water (40 mL) and stirred for 15min. The precipitate was filtered, washed with water (5 mL). The residuepurified by column chromatography, eluting with a gradient (20-50%) ofEtOAc/pet. ether, to give benzoate 22 (112 mg, 26%) as a white powder:mp (EtOAc) 190-192° C.; ¹H NMR (CDCl₃) δ 8.05 (ddd, J=8.6, 1.8, 1.5 Hz,2H, H-2, H-6), 7.89 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-3, H-5), 7.71 (ddd,J=8.6, 2.2, 1.8 Hz, 2H, H-2′, H-6′), 7.51 (ddd, J=8.6, 2.2, 1.8 Hz, 2H,H-3′, H-5′), 4.30 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃), 2.32 (s, 3H,CH₃), 1.33 [s, 9H, C(CH₃)₃]; MS m/z 428.5 (MH⁺, 100%). Anal. calcd forC₂₃H₂₅NO₅S: C, 64.62; H, 5.89; N, 3.28. Found: C, 64.70; H, 5.94; N,3.25%.

4-(4-{[(4-tert-Butylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (23)

Method C.

Reaction of benzoate 22 (97 mg, 0.23 mmol) and 6 M HCl (5 mL) gave acid23 (85 mg, 89%) as a white solid: mp (H₂O) 220-222° C.; ¹H NMR δ 13.15(br s, 1H, CO₂H), 8.02 (dd, J=8.7, 1.9 Hz, 2H, H-2, H-6), 7.88 (ddd,J=8.7, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.70 (ddd, J=8.6, 2.0, 1.9 Hz, 2H,H-2′, H-6′), 7.63 (ddd, J=8.6, 2.0, 1.9 Hz, 2H, H-3′, H-5′), 4.64 (s,2H, CH₂SO₂), 2.14 (s, 3H, CH₃), 1.29 [s, 9H, C(CH₃)₃]; MS m/z 415.5(MH⁺, 100%). Anal. calcd for C₂₂H₂₃NO₅S.H₂O: C, 61.24; H, 5.84; N, 3.25.Found: C, 61.32; H, 5.50; N, 3.14%.

4-(4-{[(4-tert-Butylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(24)

Method E.

Reaction of oxalyl chloride (27 λL, 0.31 mmol) and benzoic acid 23 (85mg, 0.21 mmol) with subsequent coupling to 3-pyridinylmethylamine (23λL, 0.23 mmol) gave benzamide 24 (49 mg, 46%) as a white powder: mp(EtOAc) 177-180° C.; ¹H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.57 (d,J=1.8 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 7.98 (br d,J=8.5 Hz, 2H, H-2, H-6), 7.86 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.73 (brdt, J=7.9, 1.9 Hz, 1H, H-4′), 7.70 (br dd, J=8.6, 1.9 Hz, 2H, H-2″,H-6″), 7.63 (br dd, J=8.6, 1.9 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.89,4.7, 0.6 Hz, 1H, H-5′), 4.60 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H,CH₂N), 2.14 (s, 3H, CH₃), 1.30 [s, 9H, C(CH₃)₃]; ¹³C NMR δ 165.4, 157.8,157.0, 149.8, 148.7, 148.0, 135.4, 135.3, 135.0, 134.8, 128.7, 128.1(2), 127.9 (2), 125.9 (2), 125.3 (2), 123.3, 52.9, 40.4, 34.8, 30.6 (3),9.5, one resonance not observed; MS m/z 504.5 (MH⁺, 100%). Anal. calcdfor C₂₈H₂₉N₃O₄S.CH₃OH: C, 65.03; H, 6.21; N, 7.84. Found: C, 65.03; H,5.94; N, 7.99%.

Example 154-(4-{[(3,5-Dimethylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(27)

Methyl4-(4-{[(3,5-Dimethylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(25)

A solution of Na₂SO₃ (308 mg, 2.4 mmol) and Na₂CO₃ (259 mg, 2.4 mmol) inwater (5 mL) was added to a suspension of 3,5-dimethylbenzenesulfonylchloride (500 mg, 2.4 mmol) in water (5 mL) and the mixture was stirredat 100° C. for 2 h. The mixture was cooled, filtered, and the filtratewas made acidic with 1 M HCl and chilled at 0° C. for 2 h. Theprecipitate was filtered, washed with water (1 mL) and dried. A mixtureof chloride 2 (289 mg, 1.08 mmol) and crude sulfinic acid (184 mg, 1.08mmol) in dry DMF (10 mL) was stirred at 100° C. for 16 h. The mixturewas cooled and diluted with ice/water (50 mL) and stirred for 15 min.The precipitate was filtered, washed with water (5 mL). The residuepurified by column chromatography, eluting with a gradient (50-100%) ofEtOAc/pet. ether, to give benzoate 25 (388 mg, 90%) as a white powder:mp (EtOAc) 141-143° C.; ¹H NMR (CDCl₃) δ 8.03 (ddd, J=8.6, 1.8, 1.5 Hz,2H, H-2, H-6), 7.94 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-3, H-5), 7.42 (br s,2H, H-2′, H-6′), 7.25 (br s, 1H, H-4′), 4.28 (s, 2H, CH₂SO₂), 3.94 (s,3H, OCH₃), 2.35 (s, 3H, CH₃), 2.33 (s, 6H, 2×CH₃); MS m/z 400.5 (MH⁺,100%). Anal. calcd for C₂₁H₂₁NO₅S: C, 63.14; H, 5.30; N, 3.51. Found: C,63.23; H, 5.28; N, 3.46%.

4-(4-{[(3,5-Dimethylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (26)

Method C.

Reaction of benzoate 25 (346 mg, 0.87 mmol) and 6 M HCl (10 mL) gaveacid 26 (335 mg, 100%) as a white solid: mp (H₂O) 265-268° C.; ¹H NMR δ13.16 (br s, 1H, CO₂H), 8.05 (dd, J=8.5, 1.8 Hz, 2H, H-2, H-6), 7.93(ddd, J=8.5, 1.8 Hz, 2H, H-3, H-5), 7.41 (br s, 2H, H-2′, H-6′), 7.37(br s, 1H, H-4′), 4.62 (s, 2H, CH₂SO₂), 2.32 (s, 6H, 2×CH₃), 2.19 (s,3H, CH₃); MS m/z 386.5 MH⁺, 100%). Anal. calcd for C₂₀H₁₉NO₅S: C, 62.32;H, 4.97; N, 3.63. Found: C, 62.59; H, 4.84; N, 3.58%.

-(4-{[(3,5-Dimethylphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(27)

Method E.

Reaction of oxalyl chloride (106 λL, 1.21 mmol) and benzoic acid 26 (311mg, 0.81 mmol) with subsequent coupling to 3-pyridinylmethylamine (91λL, 0.89 mmol) gave benzamide 27 (302 mg, 78%) as a white powder: mp(EtOAc) 188-190° C.; ¹H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.57 (d,J=1.6 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.00 (d, J=8.5Hz, 2H, H-2, H-6), 7.91 (d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.8Hz, 1H, H-4′), 7.41 (br s, 2H, H-2″, H-6″), 7.33-7.38 (m, 2H, H-5′,H-4″), 4.61 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 2.32 (s, 6H,2×CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR δ 165.6, 157.9, 150.0, 148.9, 148.1,138.8, 138.5 (2), 135.4, 135.3, 135.2, 135.0, 134.9, 128.9, 128.1 (2),125.6 (2), 125.4 (2), 123.4, 52.9, 40.5, 20.6 (2), 9.7; MS m/z 476.5(MH⁺, 100%). Anal. calcd for C₂₆H₂₅N₃O₄S: C, 65.67; H, 5.30; N, 8.84.Found: C, 65.91; H, 5.38; N, 8.89%.

Example 164-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(30)

Methyl4-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(28)

Method B.

Reaction of chloride 2 (404 mg, 1.52 mmol), 4-bromobenzenethiol (317 mg,1.60 mmol) and K₂CO₃ (202 mg, 1.60 mmol) in dry DMF (40 mL) withsubsequent oxidation by mCPBA (1.31 g, 3.8 mmol) gave benzoate 28 (353mg, 52%) as a white powder: mp (EtOAc) 186-188° C.; ¹H NMR (CDCl₃) δ8.09 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-2, H-6), 7.89 (ddd, J=8.6, 1.8, 1.5Hz, 2H, H-3, H-5), 7.63-7.68 (m, 4H, H-2′, H-3′, H-5′, H-6′), 4.31 (s,2H, CH₂SO₂), 3.94 (s, 3H, OCH₃), 2.38 (s, 3H, CH₃); MS m/z 450.0 (MH⁺,100%), 452.0 (MH⁺, 100%). Anal. calcd for C₁₉H₁₆BrNO₅S: C, 50.68; H,3.58; N, 3.11. Found: C, 51.02; H, 3.62; N, 3.24%.

4-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (29)

Method D.

Reaction of benzoate 28 (320 mg, 0.71 mmol) and 2 M NaOH (10 mL) indioxane (10 mL) gave acid 29 (216 mg, 70%) as a white solid: mp(DCM)>310° C.; ¹H NMR δ 13.15 (br s, 1H, CO₂H), 7.93 (br d, J=8.3 Hz,2H, H-2, H-6), 7.84 (ddd, J=8.6, 2.3, 1.7 Hz, 2H, H-2′, H-6′), 7.68-7.73(m, 4H, H-3, H-5, H-3′, H-5′), 4.70 (s, 2H, CH₂SO₂), 2.19 (s, 3H, CH₃);MS m/z 437.0 (MH⁺, 100%), 439.0 (MH⁺, 100%). Anal. calcd forC₁₈H₁₄BrNO₅S.½CH₂Cl₂: C, 47.08; H, 3.12; N, 2.89. Found: C, 47.09; H,2.80; N, 2.99%.

4-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(30)

Method E.

Reaction of oxalyl chloride (61 λL, 0.70 mmol) and benzoic acid 29 (204mg, 0.47 mmol) with subsequent couping to 3-pyridinylmethylamine (53 λL,0.52 mmol) gave benzamide 30 (123 mg, 50%) as a white powder: mp (EtOAc)224-227° C.; ¹H NMR δ 9.20 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.7 Hz,1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.6 Hz, 2H,H-2, H-6), 7.88 (d, J=8.6 Hz, 2H, H-3, H-5), 7.85 (ddd, J=8.6, 2.3, 1.9Hz, 2H, H-2″, H-6″), 7.70-7.76 (m, 3H, H-4′, H-3″, H-5″), 7.36 (ddd,J=7.8, 4.7, 0.6 Hz, 1H, H-5′), 4.73 (s, 2H, CH₂SO₂), 4.51 (d, J=5.9 Hz,2H, CH₂N), 2.22 (s, 3H, CH₃); ¹³C NMR δ 165.5, 158.1, 150.0, 148.9,148.1, 137.8, 135.5, 135.2, 134.9, 132.3 (2), 130.4 (2), 128.8, 128.2,128.1 (2), 125.7, 125.4 (2), 123.5, 52.8, 40.5, 9.7; MS m/z 526.1 (MH⁺,100%), 528.1 (MH⁺, 100%). Anal. calcd for C₂₄H₂₀BrN₃O₄S.½H₂O: C, 52.95;H, 4.07; N, 7.72. Found: C, 52.74; H, 3.67; N, 7.60%.

Alternate preparation of4-(4-{[(4-Bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(30)

Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) weresuccessively added and the reaction mixture was stirred at 20° C. for 10min. 3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was subsequently addedand the reaction mixture was stirred at 20° C. for 1 h. The reactionmixture was diluted with EtOAc (150 mL), washed with H₂O (3×50 mL),washed with brine (50 mL) and dried. The solvent evaporated and theresidue was purified by column chromatography, eluting with a gradient(0-10%) MeOH/EtOAc, to afford benzamide 30 (170 mg, 94%) as a whitesolid: mp (EtOAc) 225-226° C.; spectroscopically identical to the sampleprepare above.

Example 174-(5-Methyl-4-{[(3-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(33)

Methyl4-(5-Methyl-4-{[(3-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoate(31)

Method B.

Reaction of chloride 2 (267 mg, 1.00 mmol), 3-methylbenzenethiol (130mg, 1.05 mmol) and K₂CO₃ (133 mg, 2.5 mmol) in dry DMF (10 mL) withsubsequent oxidation by mCPBA (0.86 g, 2.83 mmol) gave benzoate 31 (231mg, 60%) as a white powder: mp (EtOAc) 161-163° C.; ¹H NMR (CDCl₃) δ8.08 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.92 (ddd, J=8.6, 1.9, 1.5Hz, 2H, H-3, H-5), 7.59-7.64 (m, 2H, H-2′, H-6′), 7.37-7.45 (m, 2H,H-3′, H-4′), 4.30 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃), 2.38 (s, 3H,CH₃), 2.33 (s, 3H, CH₃); MS m/z 386.6 (MH⁺, 100%). Anal. calcd forC₂₀H₁₉NO₅S: C, 62.33; H, 4.97; N, 3.63. Found: C, 62.77; H, 4.94; N,3.71%.

4-(5-Methyl-4-{[(3-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoicAcid (32)

Method C.

Reaction of benzoate 31 (217 mg, 0.56 mmol) and 6 M HCl (10 mL) gaveacid 32 (173 mg, 83%) as a white solid: mp (H₂O) 287-290° C.; ¹H NMR δ13.16 (br s, 1H, CO₂H), 8.05 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.92 (br d,J=8.5 Hz, 2H, H-3, H-5), 7.63 (br s, 1H, H-2′), 7.54-7.59 (m, 2H, H-4′,H-6′), 7.50 (t, J=7.6 Hz, 1H, H-5′), 4.65 (s, 2H, CH₂SO₂), 2.37 (s, 3H,CH₃), 2.16 (s, 3H, CH₃); MS m/z 372.6 (MH⁺, 100%). Anal. calcd forC₁₉H₁₇NO₅S: C, 61.74; H, 4.61; N, 3.77. Found: C, 61.51; H, 4.56; N,3.80%.

4-(5-Methyl-4-{[(3-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(33)

Method E.

Reaction of oxalyl chloride (56 λL, 0.64 mmol) and benzoic acid 32 (158mg, 0.43 mmol) with subsequent coupling to 3-pyridinylmethylamine (48λL, 0.47 mmol) gave benzamide 33 (79 mg, 40%) as a white powder: mp(EtOAc) 179-181° C.; ¹H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.57 (d,J=1.8 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.5Hz, 2H, H-2, H-6), 7.90 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (dt, J=7.9,1.9 Hz, 1H, H-4′), 7.63 (br s, 1H, H, H-2″) 7.53-7.60 (m, 2H, H-4″,H-6″), 7.50 (t, J=7.6 Hz, 1H, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.5 Hz, 1H,H-5′), 4.65 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 2.37 (s, 3H,CH₃), 2.16 (s, 3H, CH₃); ¹³C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0,139.0, 138.3, 135.3, 135.1, 134.8, 134.3, 128.9, 128.7, 128.3, 128.0(2), 125.8, 125.3 (2), 125.2, 123.3, 52.8, 40.4, 20.6, 9.67; MS m/z462.8 (MH⁺, 100%). Anal. calcd for C₂₅H₂₃N₃O₄S: C, 64.06, 5.02; N, 9.10.Found: C, 64.76; H, 5.06; N, 9.05%.

Example 184-(4-{[(4-Methoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(36)

Methyl4-(4-{[(4-Methoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(34)

Method B.

Reaction of chloride 2 (320 mg, 1.20 mmol), 4-methoxybenzenethiol (187mg, 1.32 mmol) and K₂CO₃ (182 mg, 1.44 mmol) in dry DMF (10 mL) withsubsequent oxidation by mCPBA (1.04 g, 3.0 mmol) gave benzoate 34 (383mg, 80%) as a white powder: mp (EtOAc) 197-199° C.; ¹H NMR (CDCl₃) δ8.08 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.93 (ddd, J=8.6, 1.9, 1.5Hz, 2H, H-3, H-5), 7.72 (ddd, J=9.0, 2.9, 2.1 Hz, 2H, H-2′, H-6′), 6.96(ddd, J=9.0, 2.9, 2.0 Hz, 2H, H-3′, H-5′), 4.29 (s, 2H, CH₂SO₂), 3.94(s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 2.33 (s, 3H, CH₃); MS m/z 402.5 (MH⁺,100%). Anal. calcd for C₂₀H₁₉NO₆S: C, 59.84; H, 4.77; N, 3.49. Found: C,59.83; H, 4.71; N, 3.45%.

4-(4-{[(4-Methoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (35)

Method D.

Reaction of benzoate 34 (285 mg, 0.71 mmol) and 2 M NaOH (10 mL) indioxane (10 mL) gave acid 35 (246 mg, 89%) as a white solid: mp (H₂O)245-248° C.; ¹H NMR [(CD₃)₂SO] δ 13.16 (br s, 1H, CO₂H), 8.05 (dd,J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.93 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5),7.70 (ddd, J=9.0, 2.9, 2.0 Hz, 2H, H-2′, H-6′), 7.13 (ddd, J=9.0, 2.9,2.0 Hz, 2H, H-3′, H-5′), 4.61 (s, 2H, CH₂SO₂), 3.84 (s, 3H, OCH₃), 2.14(s, 3H, CH₃); MS m/z 388.5 (MH⁺, 100%). Anal. calcd for C₁₉H₁₇NO₆S: C,58.91; H, 4.42; N, 3.62. Found: C, 58.86; H, 4.22; N, 3.54%.

4-(4-{[(4-Methoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(36)

Method E.

Reaction of oxalyl chloride (76 λL, 0.88 mmol) and benzoic acid 35 (226mg, 0.58 mmol) with subsequent coupling to 3-pyridinylmethylamine (65λL, 0.64 mmol) gave benzamide 36 (142 mg, 51%) as a white powder: mp(MeOH/EtOAc) 189-191° C.; ¹H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57(d, J=1.7 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (dd,J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.91 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5),7.74 (ddd, J=8.0, 2.1, 1.4 Hz, 1H, H-4′), 7.70 (ddd, J=8.9, 3.0, 2.0 Hz,2H, H-2″, H-6″), 7.36 (ddd, J=7.9, 4.7, 0.7 Hz, 1H, H-5′), 7.13 (ddd,J=8.9, 3.0, 2.0 Hz, 2H, H-3″, H-5″), 4.60 (s, 2H, CH₂SO₂), 4.51 (d,J=5.8 Hz, 2H, CH₂N), 3.84 (s, 3H, OCH₃), 2.13 (s, 3H, CH₃); ¹³C NMR δ165.5, 163.3, 157.9, 149.8, 148.9, 148.0, 135.3, 135.1, 134.8, 130.4(2), 129.8, 128.8, 128.0 (2), 126.1, 125.3 (2), 123.4, 114.3 (2), 55.7,53.0, 40.4, 9.6; MS m/z 477.6 (MH⁺, 100%). Anal. calcd forC₂₅H₂₃N₃O₅S.½CH₃OH: C, 62.06; H, 5.11; N, 8.51. Found: C, 61.85; H,4.88; N, 8.62%.

Example 194-(5-Methyl-4-{[(3-methoxyphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(39)

Methyl4-(5-Methyl-4-{[(3-methoxyphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoate(37)

Method B.

A mixture of chloride 2 (300 mg, 1.13 mmol), 3-methoxybenzenethiol (174mg, 1.24 mmol) and K₂CO₃ (171 mg, 1.36 mmol) in dry DMF (10 mL) withsubsequent oxidation by mCPBA (0.98 g, 2.83 mmol) gave benzoate 37 (240mg, 53%) as a white powder: mp (EtOAc) 156-159° C.; ¹H NMR (CDCl₃) δ8.08 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.94 (ddd, J=8.6, 1.9, 1.5Hz, 2H, H-3, H-5), 7.40-7.43 (m, 2H, H-2′, H-6′), 7.29-7.32 (m, 1H,H-4′), 7.14-7.18 (m, 1H, H-5′), 4.32 (s, 2H, CH₂SO₂), 3.94 (s, 3H,OCH₃), 3.78 (s, 3H, OCH₃), 2.34 (s, 3H, CH₃); MS m/z 402.6 (MH⁺, 100%).Anal. calcd for C₂₀H₁₉NO₆S.¼CH₃CO₂CH₂CH₃: C, 59.56; H, 5.00; N, 3.31.Found: C, 59.64; H, 4.70; N, 3.44%.

4-(5-Methyl-4-{[(3-methoxyphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoicAcid (38)

Method D.

Reaction of benzoate 37 (213 mg, 0.53 mmol) and 2 M NaOH (10 mL) indioxane (10 mL) gave acid 38 (160 mg, 78%) as a white solid: mp (H₂O)280-283° C.; ¹H NMR δ 13.12 (br s, 1H, CO₂H), 8.05 (dd, J=8.6, 1.8 Hz,2H, H-2, H-6), 7.93 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.53 (dd, J=8.9,7.7 Hz, 1H, H-5′), 7.35 (dt, J=7.7, 1.2 Hz, 1H, H-6′), 7.27-7.33 (m, 2H,H-2′, H-4′), 4.70 (s, 2H, CH₂SO₂), 3.79 (s, 3H, OCH₃), 2.18 (s, 3H,CH₃); MS m/z 388.5 (MH⁺, 100%). Anal. calcd for C₁₉H₁₇NO₆S.¼H₂O: C,58.23; H, 4.50; N, 3.57. Found: C, 57.89; H, 4.37; N, 3.43%.

4-(5-Methyl-4-{[(3-methoxyphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(39)

Method E.

Reaction of oxalyl chloride (50 λL, 0.57 mmol) and benzoic acid 38 (146mg, 0.38 mmol) with subsequent coupling to 3-pyridinylmethylamine (43λL, 0.42 mmol) gave benzamide 39 (47 mg, 26%) as a white powder: mp(EtOAc) 143-145° C.; ¹H NMR δ 9.23 (t, J=5.8 Hz, 1H, CONH), 8.56 (d,J=1.6 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (br d,J=8.5 Hz, 2H, H-2, H-6), 7.91 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (brd, J=7.9 Hz, 1H, H-4′), 7.53 (br dd, J=8.9, 7.6 Hz, 1H, H-5″), 7.34-7.39(m, 2H, H-5′, H-2″), 7.25-7.29 (m, 2H, H-4″, H-6″), 4.70 (s, 2H,CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 3.79 (s, 3H, OCH₃), 2.17 (s, 3H,CH₃); ¹³C NMR δ 165.5, 159.4, 158.0, 150.1, 148.9, 148.1, 139.7, 135.4,135.2, 134.9, 130.4, 128.8, 128.1 (2), 125.9, 125.4 (2), 123.5, 120.3,120.1, 112.8, 55.6, 52.7, 40.5, 9.7; MS m/z 478.6 (MH⁺, 100%). Anal.calcd for C₂₅H₂₃N₃O₅S.½CH₃OH: C, 62.06, 5.11; N, 8.51. Found: C, 62.23;H, 4.90; N, 8.66%.

Example 204-(4-{[(3,4-Dimethoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(42)

Methyl4-(4-{[(3,4-Dimethoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(40)

Method B.

A mixture of chloride 2 (331 mg, 1.24 mmol), 3,4-dimethoxybenzenethiol(232 mg, 1.36 mmol) and K₂CO₃ (205 mg, 1.48 mmol) in dry DMF (10 mL)with subsequent oxidation by mCPBA (1.07 g, 3.10 mmol) gave benzoate 40(375 mg, 70%) as a white powder: mp (EtOAc) 168-170° C.; ¹H NMR (CDCl₃)δ 8.09 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.95 (ddd, J=8.6, 1.9,1.5 Hz, 2H, H-3, H-5), 7.43 (dd, J=8.5, 2.1 Hz, 1H, H-6′), 7.22 (d,J=2.1 Hz, 1H, H-2′), 6.93 (d, J=8.5 Hz, 1H, H-5′), 4.30 (s, 2H, CH₂SO₂),3.94 (s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 2.36 (s, 3H,CH₃); MS m/z 432.5 (MH⁺, 100%). Anal. calcd for C₂₁H₂₁NO₇S: C, 58.46; H,4.91; N, 3.25. Found: C, 58.33; H, 4.93; N, 3.20%.

4-(4-{[(3,4-Dimethoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicacid (41)

Method D.

Reaction of benzoate 40 (355 mg, 0.82 mmol) and 2 M NaOH (10 mL) indioxane (10 mL) gave acid 41 (329 mg, 96%) as a white solid: mp (H₂O)221-223° C.; ¹H NMR δ 13.16 (br s, 1H, CO₂H), 8.05 (d, J=8.4 Hz, 2H,H-2, H-6), 7.94 (d, J=8.4 Hz, 2H, H-3, H-5), 7.33 (dd, J=8.5, 2.0 Hz,1H, H-6′), 7.26 (d, J=2.0 Hz, 1H, H-2′), 7.14 (d, J=8.5 Hz, 1H, H-5′),4.63 (s, 2H, CH₂SO₂), 3.84 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 2.16 (s,3H, CH₃); MS m/z 418.6 (MH⁺, 100%). Anal. calcd for C₂₀H₁₉NO₇S.½H₂O: C,56.33; H, 4.73; N, 3.29. Found: C, 56.02; H, 4.59; N, 3.36%.

4-(4-{[(3,4-Dimethoxyphenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(42)

Method E.

Reaction of oxalyl chloride (92 λL, 1.06 mmol) and benzoic acid 41 (294mg, 0.70 mmol) with subsequent coupling to 3-pyridinylmethylamine (78λL, 0.77 mmol) gave benzamide 42 (263 mg, 74%) as a white powder: mp(EtOAc) 104-108° C.; ¹H NMR δ 9.23 (t, J=5.9 Hz, 1H, CONH), 8.57 (d,J=1.6 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.01 (d, J=8.5Hz, 2H, H-2, H-6), 7.92 (d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.5Hz, 1H, H-4′), 7.37 (dd, J=7.5, 4.8 Hz, 1H, H-5′), 7.33 (dd, J=8.5, 2.1Hz, 1H, H-6″), 7.25 (d, J=2.1 Hz, 1H, H-2″), 7.14 (d, J=8.5 Hz, 1H,H-5″), 4.63 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 3.84 (s, 3H,OCH₃), 3.76 (s, 3H, OCH₃), 2.15 (s, 3H, CH₃); ¹³C NMR δ 165.5, 157.9,153.1, 149.9, 148.8, 148.6, 148.0, 135.3, 135.1, 134.8, 129.7, 128.8,128.0 (2), 126.2, 125.3 (2), 123.4, 122.2, 111.2, 110.6, 55.9, 55.7,52.9, 40.4, 9.6; MS m/z 508.7 (MH⁺, 100%). Anal. calcd forC₂₆H₂₅N₃O₆S.¾CH₃OH: C, 60.44, 5.31; N, 7.90. Found: C, 60.58; H, 5.17;N, 7.63%.

Example 214-(5-Methyl-4-{[(2,4-dimethylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(45)

Methyl4-(5-Methyl-4-{[(2,4-dimethylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoate(43)

Method B.

Reaction of chloride 2 (304 mg, 1.14 mmol), 2,4-dimethylbenzenethiol(174 mg, 1.26 mmol) and K₂CO₃ (173 mg, 1.37 mmol) in dry DMF (10 mL)with subsequent oxidation by mCPBA (984 mg, 2.85 mmol) gave benzoate 43(136 mg, 30%) as a white powder: mp (EtOAc) 141-143° C.; ¹H NMR (CDCl₃)δ 8.06 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br dd, J=8.6, 1.8 Hz, 2H,H-3, H-5), 7.70 (br d, J=8.1 Hz, 1H, H-6′), 7.13 (br s, 1H, H-3′), 7.06(br d, J=8.1 Hz, 1H, H-5′), 4.32 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃),2.63 (s, 3H, CH₃), 2.35 (s, 3H, CH₃); MS m/z 400.6 (MH⁺, 100%). Anal.calcd for C₂₁H₂₁NO₅S.¼CH₃CO₂CH₂CH₃: C, 62.69; H, 5.50; N, 3.32. Found:C, 62.52; H, 5.27; N, 3.48%.

4-(5-Methyl-4-{[(2,4-dimethylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)benzoicAcid (44)

Method D.

Reaction of benzoate 43 (131 mg, 0.34 mmol) and 1 M NaOH (10 mL) indioxane (10 mL) gave acid 44 (109 mg, 83%) as a white solid: mp (H₂O)235-238° C.; ¹H NMR δ 13.15 (br s, 1H, CO₂H), 8.06 (br d, J=8.5 Hz, 2H,H-2, H-6), 7.90 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.57 (d, J=8.1 Hz, 1H,H-6′), 7.28 (br s, 1H, H-3′), 7.17 (br d, J=8.1 Hz, 1H, H-5′), 4.61 (s,2H, CH₂SO₂), 2.56 (s, 3H, CH₃), 2.33 (s, 3H, CH₃), 2.16 (s, 3H, CH₃); MSm/z 386.5 (MH⁺, 100%). Anal. calcd for C₂₀H₁₉NO₅S.¾H₂O: C, 62.69; H,5.50; N, 3.32. Found: C, 62.52; H, 5.27; N, 3.48%.

4-(5-Methyl-4-{[(2,4-dimethylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(45)

Method E.

Reaction of oxalyl chloride (31 λL, 0.35 mmol) and benzoic acid 44 (92mg, 0.24 mmol) with subsequent coupling to 3-pyridinylmethylamine (27λL, 0.26 mmol) gave benzamide 45 (27 mg, 24%) as a clear gum: ¹H NMR δ9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.5 Hz, 1H, H-2′), 8.47 (dd,J=4.7, 1.5 Hz, 1H, H-6′), 8.00 (d, J=8.4 Hz, 2H, H-2, H-6), 7.88 (d,J=8.4 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.57 (d, J=8.1Hz, 1H, H-5″) 7.37 (dd, J=7.8, 4.7 Hz, 1H, H-5′), 7.27 (br s, 1H, H-3″),7.18 (d, J=8.1 Hz, 1H, H-6″), 4.61 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz,2H, CH₂N), 2.55 (s, 3H, CH₃), 2.34 (s, 3H, CH₃), 2.15 (s, 3H, CH₃); MSm/z 476.6 (MH⁺, 100%). Anal. calcd for C₂₆H₂₅N₃O₄S.½CH₃CO₂CH₂CH₃: C,64.72; H, 5.63; N, 8.09. Found: C, 64.72; H, 5.60; N, 7.75%.

Example 224-(4-{[(4-Fluorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(48)

Methyl4-(4-{[(4-Fluorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate(46)

Method B.

Reaction of chloride 2 (275 mg, 1.04 mmol), 4-methoxybenzenethiol (146mg, 1.14 mmol) and K₂CO₃ (158 mg, 1.25 mmol) in dry DMF (10 mL) withsubsequent oxidation by mCPBA (0.90 g, 2.6 mmol) gave benzoate 46 (249mg, 61%) as a white powder: mp (EtOAc) 178-181° C.; ¹H NMR (CDCl₃) δ8.07 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.91 (ddd, J=8.6, 1.9, 1.5Hz, 2H, H-3, H-5), 7.80-7.85 (m, 2H, H-2′, H-6′), 7.16-7.21 (m, 2H,H-3′, H-5′), 4.32 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃), 2.33 (s, 3H,CH₃); MS m/z 390.6 (MH⁺, 100%). Anal. calcd for C₁₉H₁₆FNO₅S: C, 58.60;H, 4.14; N, 3.60. Found: C, 58.72; H, 4.00; N, 3.54%.

4-(4-{[(4-Fluorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzoicAcid (47)

Method D.

Reaction of benzoate 46 (491 mg, 1.26 mmol) and 1 M NaOH (10 mL) indioxane (10 mL) gave acid 47 (354 mg, 75%) as a white solid: mp (H₂O)269-272° C.; ¹H NMR δ 13.20 (br s, 1H, CO₂H), 8.05 (d, J=8.5 Hz, 2H,H-2, H-6), 7.91 (d, J=8.5 Hz, 2H, H-3, H-5), 7.84-7.89 (m, 2H, H-2′,H-6′), 7.47 (br t, J=8.8 Hz, 2H, H-3′, H-5′), 4.74 (s, 2H, CH₂SO₂), 2.06(s, 3H, CH₃); MS m/z 376.5 (MH⁺, 100%). Anal. calcd forC₁₈H₁₄FNO₅S.¼H₂O: C, 56.91; H, 3.85; N, 3.69. Found: C, 57.15; H, 3.63;N, 3.59%.

4-(4-{[(4-Fluorophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(48)

Method E.

Reaction of oxalyl chloride (118 λL, 1.35 mmol) and benzoic acid 47 (337mg, 0.90 mmol) with subsequent coupling to 3-pyridinylmethylamine (101λL, 0.99 mmol) gave benzamide 48 (325 mg, 78%) as a white powder: mp(EtOAc) 218-220° C.; ¹H NMR δ 9.22 (t, J=5.9 Hz, 1H, CONH), 8.57 (d,J=1.6 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (d, J=8.5Hz, 2H, H-2, H-6), 7.83-7.91 (m, 4H, H-3, H-5, H-2″, H-6″), 7.74 (br d,J=7.8 Hz, 1H, H-4′), 7.47 (br t, J=8.8 Hz, 2H, H-3″, H-5″), 7.36 (dd,J=8.8, 4.7 Hz, 1H, H-5′), 4.73 (s, 2H, CH₂SO₂), 4.51 (d, J=5.9 Hz, 2H,CH₂N), 2.19 (s, 3H, CH₃); ¹³C NMR δ 165.5, 165.2 (d, J=252.7), 158.1,150.0, 148.9, 148.1, 135.4, 135.2, 134.9, 134.8 (d, J=2.9 Hz), 131.6 (2,d, J=9.9 Hz), 128.8, 128.1 (2), 125.8, 125.4 (2), 123.5, 116.4 (2,J=22.8 Hz), 52.8, 40.5, 9.7; MS m/z 466.6 (MH⁺, 100%). Anal. calcd forC₂₄H₂₀FN₃O₄S: C, 61.92; H, 4.33; N, 9.03. Found: C, 62.18; H, 4.38; N,9.14%.

Example 234-[5-Methyl-4-({[4-(4-methyl-1-piperazinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(49)

4-[5-Methyl-4-({[4-(4-methyl-1-piperazinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(49)

A mixture of fluoride 48 (112 mg, 0.24 mmol) and 1-methylpiperazine (1mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. Thesolvent was evaporated and the residue was suspended in ice/water (50mL) for 1 h. The mixture was partitioned between CHCl₃ (200 mL) andwater (50 mL) and the solvent evaporated. The mixture was dissolved inEtOAc (5 mL) and the precipitated filtered to give benzamide 49 (41 mg,31%) as a white powder: mp (EtOAc) 210-215° C.; ¹H NMR δ 9.23 (s, 1H,CONH), 8.56 (br s, 1H, H-2′), 8.46 (dd, J=4.8, 1.6 Hz, 1H, H-6′), 8.00(d, J=8.6 Hz, 2H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt,J=8.0, 2.0 Hz, 1H, H-4′), 7.50 (d, J=9.1 Hz, 2H, H-3″, H-5″), 7.36 (ddd,J=7.9, 4.7, 0.6 Hz, 1H, H-5′), 7.02 (d, J=9.1 Hz, 2H, H-2″, H-6″),4.49-4.53 (m, 4H, CH₂SO₂, CH₂N), 3.30 (br t, J=4.9 Hz, 4H, 2×CH₂N), 2.40(br t, J=4.9 Hz, 4H, 2×CH₂N), 2.20 (s, 3H, CH₃), 2.12 (s, 3H, CH₃); ¹³CNMR δ 165.5, 157.8, 154.0, 149.6, 148.8, 148.1, 135.3, 135.1, 134.9,129.7 (2), 128.8, 128.0 (2), 126.4, 125.4 (2), 123.4 (2), 113.3 (2),54.1 (2), 53.2, 46.4 (2), 45.6, 40.4, 9.6; MS m/z 546.8 (MH⁺, 100%).

Example 244-[5-Methyl-4-({[4-(4-morpholinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(50)

4-[5-Methyl-4-({[4-(4-morpholinyl)phenyl]sulfonyl}methyl)-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(50)

A mixture of fluoride 48 (103 mg, 0.22 mmol) and morpholine (2 mL) inDMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. Thesolvent was evaporated and the residue was suspended in ice/water (50mL) for 1 h. The precipitate was filtered, washed with water (5 mL) anddried. The crude solid was purified by column chromatography, elutingwith a gradient (0-10%) of MeOH/EtOAc, to give benzamide 50 (83 mg, 71%)as a white powder: mp (EtOAc) 208-210° C.; ¹H NMR δ 9.23 (s, 1H, CONH),8.57 (br s, 1H, H-2′), 8.47 (br d, J=4.5 Hz, 1H, H-6′), 8.00 (br d,J=8.5 Hz, 2H, H-2, H-6), 7.91 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (brd, J=7.8 Hz, 1H, H-4′), 7.54 (d, J=9.0 Hz, 2H, H-3″, H-5″), 7.37 (dd,J=7.8, 4.7 Hz, 1H, H-5′), 7.05 (d, J=9.0 Hz, 2H, H-2″, H-6″), 4.49-4.54(m, 4H, CH₂SO₂, CH₂N), 3.72 (br t, J=4.8 Hz, 4H, 2×CH₂O), 3.27 (br t,J=4.8 Hz, 4H, 2×CH₂N), 2.13 (s, 3H, CH₃); ¹³C NMR δ 165.5, 157.8, 154.2,149.7, 148.8, 148.0, 135.3, 135.1, 134.8, 129.7 (2), 128.8, 128.0 (2),126.4, 126.0, 125.4 (2), 123.4, 113.3 (2), 65.6 (2), 53.2, 46.7 (2),40.4, 9.6; MS m/z 533.7 (MH⁺, 100%). Anal. calcd for C₂₈H₂₈N₄O₅S: C,63.14; H, 5.30; N, 10.52. Found: C, 62.94; H, 5.18; N, 10.51%.

Example 254-(4-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-thiazol-2-yl)-N-(3-pyridinylmethyl)benzamide(54)

Methyl 4-[4-(Chloromethyl)-1,3-thiazol-2-yl]benzoate (51)

A mixture of methyl 4-cyanobenzoate (5.0 g, 31.0 mmol) and O,O-diethylhydrogen dithiophosphate (10.41 g, 62 mmol) in water (100 mL) wasstirred at 80° C. for 16 h under N₂. The mixture was cooled to 20° C.and filtered. The precipitate was washed with water (50 mL) and driedunder vacuum to give crude methyl 4-(aminocarbothioyl)benzoate (5.93 g,98%) as a yellow powder: mp (water) 181-184° C.; ¹H NMR δ 10.04 (br s,1H, NH₂), 9.65 (br s, 1H, NH₂), 7.83-8.00 (m, 4H, H-2, H-3, H-5, H-6),3.88 (s, 3H, OCH₃); MS m/z 196.5 (MH⁺, 100%). A mixture of the crudebenzoate (5.72 g, 29.2 mmol) and dichloroacetone (3.72 g, 29.3 mmol) inanhydrous DMF (50 mL) was stirred at 80° C. under N₂ for 16 h. Themixture was cooled to 20° C. and poured into ice/water (400 mL) andstirred for 30 min. The precipitate was filtered, washed with water (30mL) and dried. The residue was purified by column chromatography,eluting with a gradient (10-20%) of EtOAc/pet. ether, to give benzoate51 (5.40 g, 69%) as a white powder: mp (EtOAc/pet. ether) 110-111° C.;¹H NMR (CDCl₃) δ 8.11 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-2, H-6), 8.02(ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-3, H-5), 7.38 (s, 1H, H-5′), 4.76 (s,2H, CH₂Cl), 3.95 (s, 3H, OCH₃); MS m/z 268.6 (MH⁺, 100%). Anal. calcdfor C₁₂H₁₀ClNO₂S: C, 53.83; H, 3.76; N, 5.23. Found: C, 53.77; H, 3.72;N, 5.03%.

Methyl 4-(4-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-thiazol-2-yl)benzoate(52)

Method A.

Reaction of chloride 51 (402 mg, 1.5 mmol) and sodium4-methylbenzenesulfinate (294 mg, 1.7 mmol) in dry DMF (10 mL) gavebenzoate 52 (446 mg, 77%) as a white powder: mp (EtOAc) 160-161° C.; ¹HNMR (CDCl₃) δ 8.05 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-2, H-6), 7.77 (ddd,J=8.6, 1.9, 1.7 Hz, 2H, H-3, H-5), 7.64 (ddd, J=8.3, 1.9, 1.7 Hz, 2H,H-2″, H-6″), 7.42 (s, 1H, H-5′), 7.27 (br d, J=8.3 Hz, 2H, H-3″, H-5″),4.60 (s, 2H, CH₂SO₂), 3.94 (s, 3H, OCH₃), 2.41 (s, 3H, CH₃); MS m/z388.6 (MH⁺, 100%). Anal. calcd for C₁₉H₁₇NO₄S₂: C, 58.90; H, 4.42; N,3.61. Found: C, 58.83; H, 4.33; N, 3.55%.

4-(4-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-thiazol-2-yl)benzoic Acid(53)

Method C.

Reaction of benzoate 52 (407 mg, 1.05 mmol) and 6 M HCl (20 mL) gaveacid 53 (392 mg, 100%) as a white solid: mp (H₂O) 270-272° C.; ¹H NMR δ13.15 (br s, 1H, CO₂H), 8.01 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-2, H-6),7.83 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-3, H-5), 7.70 (s, 1H, H-5′), 7.65(br d, J=8.3, 2H, H-2″, H-6″), 7.41 (br d, J=8.3 Hz, 2H, H-3″, H-5″),4.87 (s, 2H, CH₂SO₂), 2.39 (s, 3H, CH₃); MS m/z 374.6 (MH⁺, 100%). Anal.calcd for C₁₈H₁₅NO₄S₂: C, 57.89; H, 4.05; N, 3.75. Found: C, 57.89; H,4.07; N, 3.63%.

4-(4-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-thiazol-2-yl)-N-(3-pyridinylmethyl)benzamide(54)

Method E.

Reaction of oxalyl chloride (70 λL, 0.8 mmol) and benzoic acid 53 (200mg, 0.54 mmol) with subsequent reaction with 3-pyridinylmethylamine (60λL, 0.6 mmol) gave benzamide 54 (171 mg, 68%) as a white powder: mp(EtOAc) 178-181° C.; ¹H NMR δ 9.19 (t, J=5.9 Hz, 1H, CONH), 8.57 (d,J=1.6 Hz, 1H, H-2″), 8.47 (dd, J=4.8, 1.5 Hz, 1H, H-6″), 7.97 (dd,J=6.7, 1.8 Hz, 2H, H-2, H-6), 7.81 (dd, J=6.7, 1.8 Hz, 2H, H-3, H-5),7.74 (ddd J=8.1, 2.1, 1.6 Hz, 1H, H-4″), 7.68 (s, 1H, H-5′), 7.65 (dd,J=8.3, 1.7 Hz, 2H, H-2′″, H-6″), 7.41 (br d, J=8.3 Hz, 2H, H-3′″, H-5″),7.36 (ddd, J=8.1, 4.8, 0.7 Hz, 1H, H-5″), 4.87 (s, 2H, CH₂SO₂), 4.51 (d,J=5.9 Hz, 2H, CH₂N), 2.40 (s, 3H, CH₃); ¹³C NMR δ 165.7, 165.5, 148.9,148.1, 145.2, 144.3, 135.9, 135.3, 135.2, 135.0, 134.9, 129.5 (2), 128.2(2), 128.1 (2), 125.9 (2), 123.4, 122.2, 57.0, 40.5, 21.0; MS m/z 464.8(MH⁺, 100%). Anal. calcd for C₂₄H₂₁N₃O₃S₂: C, 62.18; H, 4.57; N, 9.06.Found: C, 62.30; H, 4.55; N, 9.10%.

Example 26 Alternate Preparation of4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(9)

4-[4-(Hydroxymethyl)-5-methyl-1,3-oxazol-2-yl]benzoic Acid (55)

Method D.

Reaction of chloride 2 (500 mg, 1.88 mmol) and aqueous NaOH (2 M, 10 mL,20 mmol) gave acid 55 (313 mg, 72%) as a cream solid: mp (EtOAc/MeOH)240-242° C.; ¹H NMR δ □ 13.18 (br s, 1H, CO₂H), 8.00-8.06 (m, 4H, H-2,H-3, H-5, H-6), 5.11 (br s, 1H, OH), 2.41 (s, 3H, CH₃); MS m/z 234.5(MH⁺, 100%); HRMS calcd for C₁₂H₁₂NO₄: 234.0761. Found: 234.0760.

4-[4-(Hydroxymethyl)-5-methyl-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(56)

HBTU (170 mg, 0.45 mmol) was added to a solution of acid 55 (80 mg, 0.34mmol) and diisopropylethylamine (0.13 mL, 0.69 mmol) in anhydrous DMF (7mL). The solution was stirred at 20° C. for 10 min.3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was then added and thereaction mixture was stirred at 20° C. for 1 h. It was the diluted withDCM (300 mL) and washed with H₂O (3×50 mL) and then washed with brine(50 mL). The combined organic phase was dried, filtered and the solventevaporated. The residue was purified by column chromatography, elutingwith 10% MeOH/DCM, to give amide 56 (65 mg, 59%) as a cream powder: mp(MeOH/DCM) 182-184° C.; ¹H NMR δ 9.19 (t, J=5.7 Hz, 1H, NH), 8.57 (br s,1H, H-2′), 8.46 (br d, J=4.6 Hz, 1H, H-6′), 8.00 (s, 4H, H-2, H-3, H-5,H-6), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.36 (dd, J=7.8, 4.8 Hz, 1H,H-5′), 5.06 (t, J=5.6 Hz, 1H, OH), 4.51 (d, J=5.8 Hz, 2H, CH₂N), 4.39(d, J=5.6 Hz, 2H, CH₂O), 2.41 (s, 3H, CH₃); MS m/z 324.8 (MH⁺, 100%);Anal. calcd for C₁₈H₁₇N₃O₃.⅓H₂O: C, 65.94; H, 5.38; N, 12.82. Found: C,66.06; H, 5.20; N, 12.85.

4-(5-Methyl-4-{[(4-methylphenyl)sulfonyl]methyl}-1,3-oxazol-2-yl)-N-(3-pyridinylmethyl)benzamide(9)

A solution of alcohol 56 (163 mg, 0.5 mmol) in anhydrous DMF (7 mL) wascooled to 0° C. NEt₃ (0.14 mL, 1 mmol) and MsCl (47 λL, 0.6 mmol) wereadded successively and the reaction mixture was stirred at 0° C. for 1h. K₂CO₃ (138 mg, 1 mmol) and 4-methylthiophenol (68 mg, 0.55 mmol) wereadded and the reaction mixture was stirred at 60° C. for 1 h. Thereaction mixture was then cooled to 20° C. and partitioned between EtOAc(200 mL) and H₂O (50 mL). The organic fraction was washed with H₂O (2×50mL), washed with brine (50 mL), and dried. The solvent was evaporated togive the crude sulfide (158 mg, 0.37 mmol) which was used withoutfurther purification. A solution of Oxone® (172 mg, 0.28 mmol) in H₂O (3mL) was added at 0° C. to a stirred solution of crude sulfide (88 mg,0.2 mmol) in MeOH (3 mL), and the reaction mixture was stirred for 1 hat 20° C. H₂O was added (50 mL), the mixture was extracted with DCM(3×50 mL) and the organic phase was washed with brine (50 mL), dried,and the solvent was evaporated. Remaining sulfide (70 mg, 0.16 mmol) wastreated as described and the combined crude products were purified bycolumn chromatography, eluting with 5% MeOH/EtOAc, to give sulfone 9 (65mg, 28%) as a white powder: spectroscopically identical to the sampleprepared above.

Example 27N-Benzyl-4-(4-{[(4-bromophenyl)sulfonyl]methyl}-5-methyl-1,3-oxazol-2-yl)benzamide(57)

Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) weresuccessively added and the reaction mixture was stirred at 20° C. for 10min. Benzylamine (0.16 mL, 1.4 mmol) was added and the reaction mixturewas stirred at 20° C. for 1 h. The mixture was diluted with EtOAc (150mL), washed with H₂O (3×50 mL), washed with brine (50 mL) and dried. Thesolvent evaporated and the residue was purified by columnchromatography, eluting with a gradient (50-100%) of EtOAc/pet. etherfollowed by a gradient (1-4%) MeOH/DCM, to afford amide 57 (117 mg, 66%)as a white solid: mp (DCM/MeOH) 234-237° C.; ¹H NMR δ □ (t, J=5.9 Hz,1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.87 (br d, J=8.7 Hz,2H, H-3, H-5), 7.85 (dt, J=8.8, 2.1 Hz, 2H, H-2′, H-6′), 7.72 (dt,J=8.7, 2.1 Hz, 2H, H-3′, H-5′), 7.34 (s, 2H, H-2″, H-6″), 7.33 (s, 2H,H-3″, H-5″), 7.22-7.28 (m, 1H, H-4″), 4.74 (s, 2H, CH₂SO₂), 4.49 (d,J=5.9 Hz, 2H, CH₂NH), 2.21 (s, 3H, CH₃); ¹³C NMR δ□ 165.3, 158.0, 150.0,139.4, 137.7, 135.6, 132.2 (2), 130.3 (2), 128.6, 128.2 (2), 128.1,128.0 (2), 127.2 (2), 126.7, 125.6, 125.3 (2), 52.6, 42.6, 9.7; MS m/z526.5, 528.5 (MH⁺, 100%). Anal. calcd for C₂₅H₂₁BrN₂O₄S: C, 57.15; H,4.03; N, 5.33. Found: C, 57.34; H, 3.74; N, 5.50%.

Example 284-[4-({[4-(21-Amino-4,7,10,13,16,19-hexaoxahenicos-1-yl)phenyl]sulfonyl}methyl)-5-methyl-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(61)

tert-Butyl 3,6,9,12,15,18-Hexaoxahenicos-20-yn-1-ylcarbamate (58). Mesylchloride (1.78 mL, 23.0 mmol) was added dropwise to a stirred suspensionof hexaethylene glycol (5.42 g, 19.2 mmol) and Ag₂O (4.67 g, 20.2 mmol)in dry DCM (50 mL) at 20° C. and the mixture was stirred at 20° C. for 3days. The mixture was filtered through Celite® and the solventevaporated. The residue was purified by column chromatography, elutingwith a gradient (0-10%) of MeOH/EtOAc, to give17-hydroxy-3,6,9,12,15-pentaoxaheptadec-1-yl methanesulfonate (3.52 g,51%) as a colourless oil: ¹H NMR (CDCl₃) δ 4.36-4.40 (m, 2H, CH₂OSO₂),3.76-3.78 (m, 2H, CH₂O), 3.70-3.74 (m, 2H, CH₂O), 3.64-3.67 (m, 16H,8×CH₂O), 3.59-3.62 (m, 2H, CH₂O), 3.09 (s, 3H, SO₂CH₃), 2.80 (br s, 1H,OH); MS m/z 361.6 (MH⁺, 100%). A mixture of the mesylate (3.52 g, 9.8mmol) and NaN₃ (1.27 g, 19.5 mmol) in dry DMF (20 mL) was stirred at110° C. for 2 h. The mixture was cooled to 20° C. and the solventevaporated. The residue was purified by column chromatography, elutingwith 10% MeOH/EtOAc, to give17-azido-3,6,9,12,15-pentaoxaheptadecan-1-ol (2.98 g, 99%) as acolourless oil: ¹H NMR (CDCl₃) δ3.71-3.74 (m, 2H, CH₂O), 3.65-3.69 (m,18H, 9×CH₂O), 3.59-3.62 (m, 2H, CH₂O), 3.39 (br t, J=5.2 Hz, 2H, CH₂N₃),2.82 (br s, 1H, OH); MS m/z 308.5 (MH⁺, 100%). A mixture of azide (2.98g, 9.7 mmol) and Pd/C (100 mg) in EtOH (50 mL) was stirred under H₂ (60psi) for 1 h. The mixture was filtered through Celite® and washed withEtOH (3×20 mL) and the solvent was evaporated. The crude residue wasdissolved in DCM (50 mL) and di-tert-butyl dicarbonate (2.56 g, 11.7mmol) in DCM (20 mL) was added dropwise and the solution was stirred at20° C. for 16 h. The solvent was evaporated and residue was purified bycolumn chromatography, eluting with 10% MeOH/EtOAc, to give tert-butyl17-hydroxy-3,6,9,12,15-pentaoxaheptadec-1-ylcarbamate (2.97 g, 80%) as acolourless oil: ¹H NMR (CDCl₃) δ 5.17 (br s, 1H, NHCO₂), 3.70-3.74 (m,2H, CH₂O), 3.60-3.68 (m, 18H, 9×CH₂O), 3.54 (br t, J=5.1 Hz, 2H, CH₂O),3.31 (br q, J=5.1 Hz, 2H, CH₂N), 2.81 (br s, 1H, OH), 1.44 [s, 9H,C(CH₃)_(3]); MS m/z 382.5

(MH⁺, 100%). NaH (343 mg, 8.56 mmol) was added in small portions to astirred solution of alcohol (2.97 g, 7.8 mmol) in THF (50 mL) at 0° C.and the resulting mixture stirred at 0° C. for 30 min. Propargyl bromide(0.87 mL, 7.8 mmol) was added followed by tetrabutylammonium iodide (29mg, 78 μmol) and the mixture was stirred at 20° C. for 16 h. Thereaction was quenched with sat. aq. NH₄Cl and extracted with EtOAc (4×50mL). The combined organic fraction was washed with brine (50 mL), driedand the solvent evaporated. The residue was purified by columnchromatography, eluting with 80% EtOAc/pet. ether, to give the acetylene58 (2.56 g, 79%) as a colourless oil: ¹H NMR (CDCl₃) δ 5.05 (br s, 1H,NHCO₂), 4.20 (d, J=2.4 Hz, 2H, CH₂C≡C), 3.68-3.71 (m, 4H, 2×CH₂O),3.64-3.67 (m, 12H, 6×CH₂O), 3.60-3.63 (m, 4H, 2×CH₂O), 3.54 (br t, J=5.2Hz, 2H, CH₂O), 3.31 (br q, J=5.2 Hz, 2H, CH₂N), 2.42 (t, J=2.4 Hz, 1H,CH), 1.44 [s, 9H, C(CH₃)₃]; MS m/z 420.7 (MH⁺, 100%); HRMS calcd forC₂₀H₃₈N₄O₈S (MH⁺): m/z 420.2592. found m/z 420.2590 (0.4 ppm).

tert-Butyl21-[4-({[5-Methyl-2-(4-{[(3-pyridinylmethyl)amino]carbonyl}phenyl)-1,3-oxazol-4-yl]methyl}sulfonyl)phenyl]-3,6,9,12,15,18-hexaoxahenicos-20-yn-1-ylcarbamate(59)

PdCl₂(PPh₃)₂ (14 mg, 0.02 mmol) was added to a stirred, degassedsolution of bromide (100 mg, 0.19 mmol), acetylene 58 (105 mg, 0.25mmol) and CuI (4 mg, 0.02 mmol) in a 1:1 mixture of NEt₃/DMF (5 mL), andthe mixture was stirred in a sealed pressure vessel at 70° C. 16 h. Themixture was cooled to 20° C., diluted with EtOAc (200 mL) and washedwith water (3×50 mL), washed with brine (50 mL) and dried. The solventwas evaporated and the residue purified by column chromatography,eluting with a gradient (0-5%) of MeOH/EtOAc, to give carbamate 59 (115mg, 70%) as a white gum: ¹H NMR δ 9.22 (t, J=5.9 Hz, 1H, CONH), 8.57 (brs, 1H, H-2′), 8.47 (dd, J=4.6, 1.2 Hz, 1H, H-6′), 8.00 (br d, J=8.6 Hz,2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.79 (dd, J=6.7, 1.9Hz, 2H, H-2″, H-6″), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.68 (dd, J=6.7,1.8 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=7.7, 4.8 Hz, 1H, H-5′), 6.73 (br t,J=5.4 Hz, 1H, NHCO₂), 4.74 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz, 2H,CH₂NH), 4.45 (s, 2H, CH₂C≡C), 3.62-3.65 (m, 2H, CH₂O), 3.56-3.59 (m, 2H,CH₂O), 3.46-3.53 (m, 16H, CH₂O), 3.36 (t, J=6.1 Hz, 2H, H-20′″), 3.05(q, J=6.1 Hz, 2H, H-21′″), 2.17 (s, 3H, CH₃), 1.36 [s, 9H, (CH₃)₃]; HRMScalcd for C₄₄H₅₇N₄O₁₂S (MH⁺): m/z 865.3688. found m/z 865.3679.

tert-Butyl21-[4-({[5-Methyl-2-(4-{[(3-pyridinylmethyl)amino]carbonyl}phenyl)-1,3-oxazol-4-yl]methyl}sulfonyl)phenyl]-3,6,9,12,15,18-hexaoxahenicos-1-ylcarbamate(60)

A mixture of alkyne 59 (100 mg, 0.11 mmol) and 10% Pd/C (50 mg, 0.04mmol) in MeOH (15 mL) was stirred at 20° C. under H₂ (60 psi) for 2.5 h.The mixture was filtered through Celite®, washed with MeOH (100 mL), thesolvent was evaporated and the residue was dried to give the carbamate60 (85 mg, 85%) as a white gum, which was used in the next step withoutfurther purification: ¹H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d,J=1.8 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 7.99 (br d,J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt,J=7.9 1.9 Hz, 1H, H-4′), 7.68 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.44 (brd, J=8.3 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.9, 4.8, 0.6 Hz, 1H, H-5′),6.73 (t, J=5.5 Hz, 1H, NHCO₂), 4.64 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz,2H, CH₂NH), 3.43-3.50 (m, 20H, CH₂O), 3.36 (br t, J=6.3 Hz, 4H, H-3′″,H-20′″), 3.05 (br q, J=5.9 Hz, 2H, H-21′″), 2.71 (br t, J=7.6 Hz, 2H,H-r), 2.12 (s, 3H, CH₃), 1.79 (br q, J=7.1 Hz, 2H, H-2′″), 1.36 [s, 9H,(CH₃)₃].

4-[4-({[4-(21-Amino-4,7,10,13,16,19-hexaoxahenicos-1-yl)phenyl]sulfonyl}methyl)-5-methyl-1,3-oxazol-2-yl]-N-(3-pyridinylmethyl)benzamide(61)

A solution of carbamate 60 (85 mg, 0.098 mmol) in a mixture oftrifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20°C. for 1 h. The solvent was evaporated and the residue was purified bycolumn chromatography, eluting with 10% MeOH/DCM containing 1% aqueousNH₃, to give amine 61 (56 mg, 75%) as a white gum: ¹H NMR δ 9.22 (t,J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.7 Hz, 1H, H-2′), 8.46 (dd, J=4.8, 1.6Hz, 1H, H-6′), 7.99 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6Hz, 2H, H-3, H-5), 7.73 (dt, J=7.9, 1.9 Hz, 1H, H-4′), 7.68 (br d, J=8.3Hz, 2H, H-2″, H-6″), 7.44 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 7.36 (ddd,J=7.8, 4.8, 0.6 Hz, 1H, H-5′), 4.65 (s, 2H, CH₂SO₂), 4.51 (d, J=5.8 Hz,2H, CH₂NH), 3.49-3.50 (m, 20H, CH₂O), 3.43-3.45 (m, 2H, CH₂O), 3.33-3.36(m, 2H, CH₂O), 2.72 (t, J=7.3 Hz, 2H, H-r), 2.64 (t, J=5.6 Hz, 2H,H-21′″), 2.12 (s, 3H, CH₃), 1.79 (br q, J=7.2 Hz, 2H, H-2′″), NH₂ notobserved; ¹³C NMR δ 165.4, 157.9, 149.8, 148.8, 148.5, 148.0, 135.7,135.3, 135.1, 134.8, 129.1 (2), 128.7, 128.3 (2), 128.0 (2), 125.9,125.3 (2), 123.4, 72.6, 69.7 (7), 69.6, 69.5, 69.4, 68.9, 52.8, 41.1,40.4, 31.4, 30.4, 9.5; HRMS calcd for C₃₉H₅₃N₄O₁₀S (MH⁺): m/z 769.3477.found m/z 769.3492.

Example 294-[4-({[4-(21-Amino-4,7,10,13,16,19-hexaoxahenicos-1-yl)phenyl]sulfonyl}methyl)-5-methyl-1,3-oxazol-2-yl]-N-benzylbenzamide(63)

tert-Butyl21-(4-{[(2-{4-[(Benzylamino)carbonyl]phenyl}-5-methyl-1,3-oxazol-4-yl)methyl]sulfonyl}phenyl)-3,6,9,12,15,18-hexaoxahenicos-1-ylcarbamate(62)

PdCl₂(PPh₃)₂ (14 mg, 0.02 mmol) was added to a stirred, degassedsolution of bromide (94 mg, 0.18 mmol), acetylene 58 (105 mg, 0.25 mmol)and CuI (4 mg, 0.02 mmol) in a 1:1 mixture of NEt₃/DMF (5 mL), and themixture was stirred in a sealed pressure vessel at 70° C. 16 h. Themixture was cooled to 20° C., diluted with EtOAc (200 mL) and washedwith water (3×50 mL), washed with brine (50 mL) and dried. The solventwas evaporated and the residue purified by column chromatography,eluting with 2% MeOH/EtOAc, to give carbamate 62 (55 mg, 35%) as a creamgum: ¹H NMR δ 9.17 (t, J=6.0 Hz, 1H, CONH), 8.01 (br d, J=8.5 Hz, 2H,H-2, H-6), 7.89 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.79 (br d, J=8.5 Hz,2H, H-2″, H-6″), 7.68 (br d, J=8.5 Hz, 2H, H-3″, H-5″), 7.32-7.34 (m,4H, H-2′, H-3′, H-5′, H-6′), 7.22-7.28 (m, 1H, H-4′), 6.73 (br t, J=5.9Hz Hz, 1H, NHCO₂), 4.74 (s, 2H, CH₂SO₂), 4.49 (d, J=6.0 Hz, 2H, CH₂NH),4.45 (s, 2H, CH₂C≡C), 3.62-3.65 (m, 2H, CH₂O), 3.56-3.59 (m, 2H, CH₂O),3.48-3.52 (m, 16H, CH₂O), 3.36 (t, J=6.1 Hz, 2H, H-20′″), 3.05 (q, J=6.1Hz, 2H, H-21′″), 2.17 (s, 3H, CH₃), 1.36 [s, 9H, C(CH₃)₃]; HRMS calcdfor C₄₅H₅₈N₃O₁₂S (MH⁺): m/z 864.3736. found m/z 864.3711.

4-[4-({[4-(21-Amino-4,7,10,13,16,19-hexaoxahenicos-1-yl)phenyl]sulfonyl}methyl)-5-methyl-1,3-oxazol-2-yl]-N-benzylbenzamide(63)

A solution of carbamate 62 (55 mg, 0.064 mmol) in a mixture oftrifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20°C. for 1 h. The solvent was evaporated and the residue was purified bycolumn chromatography, eluting with 10% MeOH/DCM containing 1% aqueousNH₃, to give the amine 63 (38 mg, 78%) as a white gum: ¹H NMR δ 9.18 (t,J=5.9 Hz, 1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d,J=8.6 Hz, 2H, H-3, H-5), 7.79 (br d, J=8.5 Hz, 2H, H-2″, H-6″), 7.68 (brd, J=8.5 Hz, 2H, H-3″, H-5″), 7.33-7.34 (m, 4H, H-2′, H-3′, H-5′, H-6′),7.22-7.28 (m, 1H, H-4′), 4.74 (s, 2H, CH₂SO₂), 4.49 (d, J=5.9 Hz, 2H,CH₂NH), 4.45 (s, 2H, CH₂C≡C), 3.62-3.65 (m, 2H, CH₂O), 3.56-3.59 (m, 2H,CH₂O), 3.50-3.52 (m, 16H, CH₂O), 3.38 (t, J=5.7H, 2H, CH₂O), 2.69 (t,J=5.5 Hz, 2H, H-21′″), 2.17 (s, 3H, CH₃), NH₂ not observed; ¹³C NMR δ165.4, 158.1, 150.1, 139.5, 138.2, 135.7, 132.0 (2), 128.7, 128.6, 128.3(2), 128.1 (2), 127.4, 127.2 (2), 126.8 (2), 125.7, 125.4 (2), 90.1,84.1, 71.7, 69.8 (6), 69.7, 69.6, 69.5, 68.8, 58.0, 52.7, 42.7, 40.8,9.7; HRMS calcd for C₄₀H₅₀N₃O₁₀S (MH⁺): m/z 764.3211. found m/z769.3227.

Example 30

4-(Benzyloxycarbonylamino)methyl)benzoic acid (30)

Benzyl chloroformate (10.3 mL, 72.7 mmol) and 2 M NaOH solution (33 mL,66 mmol) were simultaneously added dropwise to a stirred solution of4-aminomethylbenzoic acid (29) (10.0 g, 66.2 mmol) in 2 M NaOH solution(33 mL) and THF (30 mL) at 0° C. The mixture was stirred at 20° C. for16 h, then the organic solvent was evaporated and the residue acidifiedwith 2 M HCl until the pH of the mixture was 2-3. The precipitate wasfiltered, washed with water (250 mL), washed with EtOH (50 mL), andfinally washed with Et₂O (100 mL). The solid was dried under vacuum togive acid 2 (16.43 g, 87%) as a white powder: mp 190-192° C. [lit. (Logeet. al., J. Enzyme Inhibit. Med. Chem. 2002, 17, 381-390) mp (toluene)194-195° C.; ¹H NMR δ 7.85 (br d, 2H, H-2, H-6), 7.82 (br t, J=6.1 Hz,1H, NHCO₂), 7.30-7.40 (m, 5H, H-2′, H-3′, H-4′, H-5′, H-6′), 7.27 (br d,J=8.2 Hz, 2H, H-3, H-5), 5.05 (s, 2H, OCH₂), 4.24 (d, J=6.1 Hz, 2H,CH₂N).

Benzyl 4-(pyridine-3-ylcarbamoyl)benzylcarbamate (31)

Reaction of benzoic acid 30 (10.0 g, 35.0 mmol) and oxalyl chloride(4.58 mL, 52.5 mmol), with subsequent reaction with 3-aminopyridine(3.62 g, 38.5 mmol) gave carbamate 31 (7.82 g, 62%) as a white solid: mp(EtOH) 207-210° C.; ¹H NMR δ 10.37 (s, 1H, NHCO), 8.92 (d, J=2.3 Hz, 1H,H-2′), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.18 (ddd, J=8.34, 2.5, 1.5Hz, 1H, H-4′), 7.93 (br d, J=8.3 Hz, 2H, H-2, H-6), 7.89 (br t, J=6.0Hz, 1H, NHCO₂), 7.41 (br d, J=8.3 Hz, 2H, H-3, H-5), 7.31-7.39 (m, 6H,H-5′, H-2″, H-3″, H-4″, H-5″, H-6″), 5.06 (s, 2H, CH₂O), 4.30 (d, J=6.2Hz, 2H, CH₂N). Anal. Calcd for C₂₁H₁₉N₃O₃: C, 69.79; H, 5.30; N, 11.63.Found: C, 69.60; H, 5.40; N, 11.63%.

4-(Aminomethyl)-N-(3-pyridinyl)benzamide dihydrobromide (32)

Reaction of carbamate 31 (2.2 g, 6.1 mmol) gave benzamide 32 (2.35 g,99%) as a white solid: mp (EtOAc) 292-296° C.; ¹H NMR δ 11.06 (s, 1H,NHCO), 9.35 (d, J=2.2 Hz, 1H, H-2′), 8.70 (ddd, J=8.5, 2.2, 1.1 Hz, 1H,H-4′), 8.64 (br d, J=5.4 Hz, 1H, H-6′), 8.31 (br s, 3H, NH₂.HBr), 8.09(br d, J=8.2 Hz, 2H, H-2, H-6), 7.96 (dd, J=8.6, 5.4 Hz, 1H, H-5′), 7.67(d, J=8.4 Hz, 2H, H-3, H-5), 5.95 (br s, 1H, pyrN.HBr), 4.16 (q, J=5.8Hz, 2H, CH₂N); Anal. Calcd for C₁₃H₁₅Br₂N₃O: C, 40.13; H, 3.89; N,10.80. Found: C, 39.99; H, 3.94; N, 10.36%.

4-(Aminomethyl)-N-(3-pyridinyl)benzamide (33)

A suspension of dihydrobromide salt 32 (1 mmol) in dilute aqueousammonia solution (50 mL) was extracted into CHCl₃ (3×50 mL), the organicfraction dried and the solvent evaporated to give crude benzamide 33which was used directly.

Example 31 N-(3-Pyridinyl)-4-{[(3-pyridylsulfonyl)amino]methyl}benzamideII-1

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (217 mg, 1.0mmol) and 2-pyridylsulfonyl chloride (170 mg, 1.0 mmol) in dry pyridine(10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated andthe residue stirred in ice/water (20 mL) for 1 h. The precipitate wasfiltered, washed with water (5 mL) and dried. The crude solid waspurified by column chromatography, eluting with a gradient (0-20%) ofMeOH/EtOAc, to give benzamide 6 (213 mg, 60%) as a white powder: mp(MeOH/EtOAc) 189-191° C.; ¹H NMR δ 10.37 (s, 1H, NHCO), 8.95 (br s, 2H,H-2′, H-2″), 8.80 (d, J=4.6 Hz, 1H, H-6′), 8.52 (br s, 1H, H-6″), 8.34(br s, 1H, NHSO₂), 8.14-8.21 (m, 2H, H-4′, H-4″), 7.90 (d, J=8.3 Hz, 2H,H-2, H-6), 7.60 (dd, J=7.9, 4.6 Hz, 1H, H-5″), 7.38-7.44 (m, 3H, H-3,H-5, H-5′), 4.18 (s, 2H, CH₂N); ¹³C NMR δ 165.5, 152.9, 147.0, 144.5,142.0, 141.4, 137.1, 134.4, 133.1, 127.7 (2), 127.5 (2), 127.3, 124.2,123.6 (2), 45.7; MS m/z 369.6 (MH⁺, 100%). Anal. calcd forC₁₈H₁₆N₄O₃S.½H₂O: C, 57.28; H, 4.54; N, 14.85. Found: C, 57.50; H, 4.33;N, 14.82%.

Example 324-({[(6-Chloro-3-pyridinyl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamideII-2

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (250 mg, 1.1mmol) and 6-chloro-3-pyridinesulfonyl chloride (233 mg, 1.1 mmol) in drypyridine (10 mL) was stirred at 20° C. for 16 h. The solvent wasevaporated and the residue stirred in ice/water (20 mL) for 1 h. Theprecipitate was filtered, washed with water (5 mL) and dried. The crudesolid was purified by column chromatography, eluting with a gradient(0-30%) of MeOH/EtOAc, to give benzamide I-2 (279 mg, 63%) as a whitepowder: mp (MeOH/EtOAc) 226-228° C.; ¹H NMR δ 10.36 (s, 1H, NHCO), 8.93(d, J=2.2 Hz, 1H, H-2′), 8.75 (dd, J=2.6, 0.6 Hz, 1H, H-2″), 8.61 (br s,1H, NHSO₂), 8.32 (dd, J=4.6, 1.5 Hz, 1H, H-6′), 8.10-8.20 (m, 2H, H-4′,H-6″), 7.90 (br d, J=8.3 Hz, 2H, H-2, H-6), 7.72 (dd, J=8.4, 0.6 Hz, 1H,H-5″), 7.36-7.42 (m, 3H, H-3, H-5, H-5′), 4.19 (s, 2H, CH₂N); ¹³C NMR δ165.4, 153.6, 147.7, 144.6, 142.0, 141.2, 137.9, 136.6, 135.8, 133.1,127.8 (2), 127.6 (2), 127.3, 125.0, 123.5, 45.7; MS m/z 404.0 (MH⁺,100%), 406.0 (MH⁺, 60%). Anal. calcd for C₁₈H₁₅ClN₄O₃S: C, 53.67; H,3.75; N, 13.91. Found: C, 53.37; H, 3.81; N, 14.03%.

Example 334-({[(6-Phenoxy-3-pyridinyl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamideII-3

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (464 mg, 2.0mmol) and 6-phenoxy-3-pyridinesulfonyl chloride (606 mg, 2.2 mmol) indry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent wasevaporated and the residue stirred in ice/water (20 mL) for 1 h. Theprecipitate was filtered, washed with water (5 mL) and dried. The crudesolid was purified by column chromatography, eluting with a gradient(0-20%) of MeOH/EtOAc, to give benzamide I-3 (405 mg, 43%) as a whitepowder: mp (MeOH/EtOAc) 203-205° C.; ¹H NMR δ 10.40 (s, 1H, CONH), 8.95(d, J=2.4 Hz, 1H, H-2′), 8.61 (t, J=6.4 Hz, 1H, NHSO₂), 8.42 (dd, J=2.5,0.4 Hz, 1H, H-2″), 8.32 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.21 (ddd, J=8.3,2.5, 1.5 Hz, 1H, H-4′), 8.12 (dd, J=8.7, 2.5, 1H, H-6″), 7.90 (br d,J=8.3 Hz, 2H, H-2, H-6), 7.37-7.43 (m, 5H, H-3, H-5, H-3′″, H-5″), 7.25(tt, J=7.4, 1.0 Hz, 1H, H-4″), 7.12-7.17 (m, 3H, H-5″, H-2′″, H-6″),4.17 (d, J=6.4 Hz, 2H, CH₂N); ¹³C NMR δ 165.4, 165.0, 152.9, 146.4,144.5, 141.9, 141.4, 138.6, 135.8, 132.9, 132.1, 129.8 (2), 127.7 (2),127.6 (2), 127.3, 125.3, 123.5, 121.5 (2), 111.5, 45.7; MS m/z 461.5(MH⁺, 100%). Anal. calcd for C₂₄H₂₀N₄O₄: C, 62.60; H, 4.38; N, 12.17.Found: C, 62.48; H, 4.41; N, 12.14%.

Example 34 N-(3-Pyridinyl)-4-{[(2-thienylsulfonyl)amino]methyl}benzamideII-4

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (256 mg, 1.1mmol) and 2-thienylsulfonyl chloride (206 mg, 1.1 mmol) in dry pyridine(10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated andthe residue stirred in ice/water (20 mL) for 1 h. The precipitate wasfiltered, washed with water (5 mL) and dried. The crude solid waspurified by column chromatography, eluting with EtOAc, to give benzamideI-4 (318 mg, 75%) as a white powder: mp (EtOAc) 185-188° C.; ¹H NMR δ10.38 (s, 1H, NHCO), 8.93 (d, J=2.2 Hz, 1H, H-2″), 8.46 (br s, 1H,NHSO₂), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.19 (ddd, J=8.2, 2.5, 1.5Hz, 1H, H-4″), 7.90-7.95 (m, 3H, H-2, H-6, H-5′), 7.61 (dd, J=3.7, 1.3Hz, 1H, H-3′), 7.43 (br d, J=8.3 Hz, 2H, H-3, H-5), 7.39 (ddd, J=8.2,4.7, 0.5 Hz, 1H, H-5″), 7.18 (dd, J=5.0, 3.7 Hz, 1H, H-4′), 4.17 (s, 2H,CH₂N); ¹³C NMR δ 165.4, 144.4, 141.9, 141.5, 141.4, 135.7, 133.0, 132.4,131.5, 127.6 (2), 127.5, 127.3 (2), 127.2, 123.4, 45.8; MS m/z 374.6(MH⁺, 100%). Anal. calcd for C₁₇H₁₅N₃O₃S₂: C, 54.67; H, 4.05; N, 11.25.Found: C, 55.23; H, 4.11; N, 11.32%.

Example 35 N-(3-Pyridinyl)-4-{[(3-thienylsulfonyl)amino]methyl}benzamideII-5

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (235 mg, 1.0mmol) and 3-thienylsulfonyl chloride (208 mg, 1.1 mmol) in dry pyridine(10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated andthe residue stirred in ice/water (20 mL) for 1 h. The precipitate wasfiltered, washed with water (5 mL) and dried. The crude solid waspurified by column chromatography, eluting with a gradient (0-10%) ofMeOH/EtOAc, to give benzamide I-5 (259 mg, 67%) as a white powder: mp(EtOAc) 207-210° C.; ¹H NMR δ 10.40 (s, 1H, CONH), 8.93 (d, J=2.2 Hz,1H, H-2″), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.23 (br t, J=6.3 Hz, 1H,NHSO₂), 8.17-8.21 (m, 2H, H-2′, H-4″), 7.92 (dd, J=8.3, 1.7 Hz, 2H, H-2,H-6), 7.75 (dd, J=5.1, 1.3 Hz, 1H, H-5′), 7.42 (br d, J=8.4 Hz, 2H, H-3,H-5), 7.39 (dd, J=8.2, 4.7 Hz, 1H, H-5″), 7.35 (dd, J=5.1, 1.3 Hz, 1H,H-4′), 4.13 (d, J=6.3 Hz, 2H, CH₂N); ¹³C NMR δ 165.5, 144.5, 141.9,141.8, 140.5, 135.7, 132.9, 130.4, 129.0, 127.6 (2), 127.3 (2), 127.2,125.1, 123.4, 45.7; MS m/z 374.6 (MH⁺, 100%). Anal. calcd forC₁₇H₁₅N₃O₃S₂: C, 54.67; H, 4.05; N, 11.25. Found: C, 54.86; H, 3.95; N,11.06%.

Example 364-({[(1,2-Dimethyl-1H-imidazol-5-yl)sulfonyl]amino}methyl)-N-(3-pyridinyl)benzamideII-6

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (341 mg, 1.5mmol) and 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (292 mg, 1.5mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. Thesolvent was evaporated and the residue stirred in ice/water (20 mL) for1 h. The precipitate was filtered, washed with water (5 mL) and dried.The crude solid was purified by column chromatography, eluting with agradient (0-20%) of MeOH/EtOAc, to give benzamide I-6 (201 mg, 35%) as awhite powder: mp (MeOH/EtOAc) 238-240° C.; ¹H NMR δ 10.37 (s, 1H, CONH),8.92 (br s, 1H, H-2′), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.18 (ddd,J=8.3, 2.5, 1.5 Hz, 1H, H-4′), 7.97 (br s, 1H, NHSO₂), 7.91 (br dd,J=8.3, 1.7 Hz, 2H, H-2, H-6), 7.61 (s, 1H, H-5″), 7.44 (br d, J=8.3 Hz,2H, H-3, H-5), 7.39 (ddd, J=8.3, 4.6, 0.6 Hz, 1H, H-5′), 4.10 (br d,J=6.0 Hz, 2H, CH₂N), 3.58 (s, 3H, NCH₃), 2.30 (s, 3H, CH₃); ¹³C NMR δ165.7, 146.4, 144.5, 142.5, 142.0, 137.1, 135.8, 132.9, 127.5 (2), 127.4(2), 127.3, 124.7, 123.5, 45.7, 32.8, 12.4; MS m/z 386.6 (MH⁺, 100%).Anal. calcd for C₁₈H₁₉N₅O₃S: C, 56.09; H, 4.97; N, 18.17. Found: C,56.15; H, 5.08; N, 18.00%.

Example 37N-(3-pyridinyl)-4-{[(4H-1,2,4-triazol-3-ylsulfonyl)amino]methyl}benzamideII-7

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (295 mg, 1.3mmol) and 4H-1,2,4-triazole-3-sulfonyl chloride (218 mg, 1.3 mmol) indry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent wasevaporated and the residue stirred in ice/water (20 mL) for 1 h. Theprecipitate was filtered, washed with water (5 mL) and dried. The crudesolid was purified by column chromatography, eluting with a gradient(0-25%) of MeOH/EtOAc, to give benzamide II-7 (176 mg, 38%) as a whitepowder: mp (MeOH/EtOAc) 266-269° C.; ¹H NMR δ 14.79 (s, 1H, NH), 10.39(s, 1H, CONH), 8.94 (d, J=2.2 Hz, 1H, H-2″), 8.78 (s, 1H, H-5′), 8.71(br s, 1H, NHSO₂), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.19 (ddd, J=8.3,2.5, 1.5 Hz, 1H, H-4″), 7.93 (d, J=8.3 Hz, 2H, H-2, H-6), 7.46 (br d,J=8.3 Hz, 2H, H-3, H-5), 7.39 (dd, J=8.3, 4.7 Hz, 1H, H-5″), 4.30 (br d,J=4.7 Hz, 2H, CH₂N); ¹³C NMR δ 165.6, 161.8, 145.7, 144.5, 142.0, 135.8,133.1, 127.7 (2), 127.3 (2), 127.2, 123.5, 45.9, 1 resonance notobserved; MS m/z 359.6 (MH⁺, 100%). Anal. calcd for C₁₅H₁₄N₆O₃S: C,50.27; H, 3.94; N, 23.45. Found: C, 50.35; H, 3.82; N, 23.42%.

Example 38 N-(3-Pyridinyl)-4-{[(2-furanylsulfonyl)amino]methyl}benzamideII-8

A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (259 mg, 1.1mmol) and 2-furanylsulfonyl chloride (209 mg, 1.2 mmol) in dry pyridine(10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated andthe residue stirred in ice/water (20 mL) for 1 h. The precipitate wasfiltered, washed with water (5 mL) and dried. The crude solid waspurified by column chromatography, eluting with a gradient (0-10%) ofMeOH/EtOAc, to give benzamide I-8 (248 mg, 61%) as a white powder: mp(EtOAc) 178-180° C.; ¹H NMR δ 10.40 (s, 1H, CONH), 8.93 (d, J=2.2 Hz,1H, H-2″), 8.69 (t, J=6.2 Hz, 1H, NHSO₂), 8.31 (dd, J=4.7, 1.5 Hz, 1H,H-6″), 8.19 (ddd, J=8.3, 2.5, 1.5 Hz, 1H, H-4″), 7.94 (dd, J=1.8, 0.9Hz, 1H, H-5′), 7.92 (br dd, J=8.3, 1.6 Hz, 2H, H-2, H-6), 7.37-7.43 (m,3H, H-3, H-5, H-5″), 7.08 (dd, J=3.4, 0.9 Hz, 1H, H-3″), 6.65 (dd,J=3.4, 1.8 Hz, 1H, H-4″), 4.20 (d, J=6.2 Hz, 2H, CH₂N); ¹³C NMR δ 165.5,148.8, 146.8, 144.5, 141.9, 141.7, 135.7, 133.0, 127.7 (2), 127.2 (3),123.4, 115.5, 111.3, 45.4; MS m/z 378.5 (MH⁺, 100%). Anal. calcd forC₁₇H₁₅N₃O₄S: C, 57.13; H, 4.23; N, 11.76. Found: C, 57.40; H, 4.19; N,11.74%.

Example 39 Synthesis of4-(5-Methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt Step 1: Synthesis of tert-butyl4-thioxopiperidine-1-carboxylate

Hydrogen sulfide gas was bubbled into a solution of tert-butyl4-oxopiperidine-1-carboxylate (2 g, 10.05 mmol, 1.00 equiv) inisopropanol (20 mL) contained in a 100-mL 3-necked round-bottom flask.The resulting solution was stirred at room temperature for 2 h. Thereaction mixture was concentrated and the crude product was used in thenext step directly without purification.

Step 2: Synthesis of tert-butyl 4-mercaptopiperidine-1-carboxylate

To a solution of crude tert-butyl 4-thioxopiperidine-1-carboxylate (2 g,9.30 mmol, 1.00 equiv) in ethanol (20 mL) contained in a 100-mL 3-neckedround-bottom flask under nitrogen was added sodium borohydride (570 mg,15.00 mmol, 1.50 equiv) in several portions. The resulting solution wasstirred at 80° C. for 2 h. The reaction mixture was then quenched by theaddition of 30 mL of water after it was cooled to room temperature witha water bath. The solution was extracted with 3×30 mL of ether and theorganic layers combined. The combined organic layer was washed with 2×50mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum to give 2.34 g of crude tert-butyl4-mercaptopiperidine-1-carboxylate as yellow oil.

Step 3: Synthesis of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate

A mixture of the crude tert-butyl 4-mercaptopiperidine-1-carboxylate(2.34 g, 10.78 mmol, 1.20 equiv), methyl4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.33 g, 8.79 mmol,1.00 equiv) and potassium carbonate (1.74 g, 12.39 mmol, 1.50 equiv) inN,N-dimethylformamide (23.4 mL) was stirred overnight in a 100-mLround-bottom flask at 50° C. The reaction mixture was then quenched bythe addition of 30 mL of water. The resulting solution was extractedwith 3×30 mL of ethyl acetate and the organic layers combined. Theorganic layer was washed with 2×40 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was elutedwith ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column togive 920 mg (23%) of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylateas a yellow solid. LC-MS: (ES, m/z): 447 [M+H]⁺, 347, 271, 146, 105.

Step 4: Synthesis of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate

To a solution of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate(920 mg, 2.06 mmol, 1.00 equiv) in chloroform (10 mL) placed in a 100-mLround-bottom flask was added m-chloroperbenzoic acid (1.78 g, 10.35mmol, 2.50 equiv) at 0° C. in small portions. The resulting solution wasstirred at 0° C. in an ice/water bath for 1 h. The mixture was washedwith 2×20 mL of aqueous sodium bisulfite solution, 2×20 mL of saturatedaqueous sodium bicarbonate solution and 2×20 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to give 0.98 g (99%) of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylateas a white solid. LC-MS: (ES, m/z): 479 [M+H]⁺, 423, 379.

Step 5: Synthesis of4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid

A solution of tert-butyl4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate(980 mg, 2.05 mmol, 1.00 equiv), sodium hydroxide (120 mg, 3.00 mmol,1.50 equiv) in ethanol (10 mL) was stirred at 50° C. overnight in a100-mL round-bottom flask. The reaction mixture was concentrated undervacuum and quenched by the addition of 30 mL of water/ice. The pH valueof the solution was adjusted to 3 with the addition of 3M hydrochloricacid. The precipitate was collected by filtration and dried to give 0.76g (80%) of4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid as a white solid. LC-MS: (ES, m/z): 409 [M-C₄H₉+H]⁺.

Step 6: Synthesis of tert-butyl4-((5-methyl-2-(4-(pyridin-3-ylmethylcarbamoyl)phenyl)oxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate

Triethylamine (440 mg, 4.36 mmol, 3.00 equiv) was added dropwise withstirring to a solution of pyridin-3-ylmethanamine (170 mg, 1.57 mmol,1.10 equiv),4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid (670 mg, 1.44 mmol, 1.00 equiv), EDCI (330 mg, 1.73 mmol, 1.20equiv) and HOBT (230 mg, 1.70 mmol, 1.20 equiv) in N,N-dimethylformamide(10 mL) contained in a 50-mL round-bottom flask. The resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched by the addition of 30 mL of water/ice. The precipitate wascollected by filtration and dried in an oven under reduced pressure togive 0.74 g (93%) of tert-butyl4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylateas a yellow solid. LC-MS: (ES, m/z): 555 [M+H]⁺, 455.

Step 7: Synthesis of4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridine-3-ylmethyl)benzamidetrifluoroacetic acid salt

Hydrogen chloride gas was bubbled into a solution of tert-butyl4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate(740 mg, 1.34 mmol, 1.00 equiv) in dichloromethane (50 mL) kept at 0° C.in a 100-mL 3-necked round-bottom flask for 3 h. The resulting solutionwas stirred for another 3 h at 0° C. The solids were collected byfiltration. The crude product (560 mg) was purified by Prep-HPLC withthe following conditions: Column, SunfireC18 19*150; mobile phase,CH3CN/0.05% aqueous TFA solution; Detector, 254 nm. The fractionscontaining the pure product were combined and concentrated in vacuum togive 109.9 mg (14%) of4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 455[M+H]⁺, 270, 228. ¹H-NMR: ¹HNMR (400 MHz, CD₃OD) δ 8.79 (1H, s),8.68-8.67 (1H, d), 8.37-8.35 (1H, d), 8.14-8.12 (1H, d), 8.02-8.00 (1H,d), 7.86-7.83 (1H, t), 4.84-4.74 (1H, s), 4.51 (1H, s), 3.61-3.57 (3H,q), 3.15-3.09 (2H, t), 2.51-2.47 (4H, d), 2.10-2.07 (2H, q).

Example 40 Synthesis of4-(5-Methyl-4-((1-methylpiperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of4-(5-methyl-4-((1-methylpiperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

4-(5-Methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide(350 mg, 0.77 mmol, 1.00 equiv) and polyoxymethylene (460 mg, 15.33mmol, 20.00 equiv) was added into a 100-mL round-bottom flask containinga mixture of methanol (10 mL), acetic acid (1 mL) and formic acid (100mL). The resulting solution was stirred overnight at 50° C. Formic acid(100 mL) was again added and the reaction mixture was stirred foranother 24 h at 110° C. The resulting mixture was concentrated undervacuum. The crude product (300 mg) was purified by Prep-HPLCchromatography with the following conditions: (1#-Pre-HPLC-005(waters)): Column, XbridgeRP 19*150; mobile phase: Phase A: water with0.05% TFA Phase B: CH₃CN Gradient: 5%-20%; Detector, UV (254/220 nm) togive 200 mg of product as its trifluoroacetic acid salt. The salt wasdissolved in 20 mL of water and the pH value of the solution wasadjusted to 10 with 1M sodium hydroxide solution. The resulting solutionwas extracted with 3×30 mL of dichloromethane and the organic layerscombined. The organic layer was washed with 3×20 mL of water, dried overanhydrous sodium sulfate and then concentrated under vacuum to give 100mg (28%) of4-(5-methyl-4-((1-methylpiperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 469 [M+H]⁺, 256, 235. ¹HNMR (400MHz, CD₃OD) δ 8.59 (1H, s), 8.47-8.46 (1H, d), 8.11-8.09 (2H, d),8.00-7.98 (2H, d), 7.90-7.88 (1H, d), 7.46-7.43 (1H, t), 4.45 (2H, s),4.41 (2H, s), 3.21-3.15 (1H, m), 3.06-3.03 (2H, d), 2.50 (3H, s), 2.30(3H, s), 2.26-2.23 (2H, d), 2.12-2.06 (2H, m), 1.96-1.87 (2H, m).

Example 41 Synthesis of4-[5-Methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt Step 1: Synthesis of tert-butylN-(4-hydroxycyclohexyl)carbamate

To a solution of 4-aminocyclohexan-1-ol (25 g, 217.06 mmol, 1.00 equiv)and di-tert-butyl dicarbonate (47.39 g, 217.14 mmol, 1.00 equiv) intoluene (250 mL) maintained under an inert atmosphere of nitrogen wasadded an aqueous sodium hydroxide (10.43 g, 260.77 mmol, 1.20 equiv)solution dropwise with stirring. The resulting solution was stirredovernight at room temperature. The solid was collected by filtrationthen dried to give 40 g (86%) of tert-butylN-(4-hydroxycyclohexyl)carbamate as a white solid.

Step 2: Synthesis of tert-butylN-[4-(methanesulfonyloxy)cyclohexyl]carbamate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (15 g,69.67 mmol, 1.00 equiv) and triethylamine (15.5 g, 153.18 mmol, 2.00equiv) in dichloromethane (150 mL) was added methanesulfonyl chloride(9.6 g, 83.81 mmol, 1.21 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 10 min at 0° C. and warmed to roomtemperature overnight. Water (100 mL) was added to quench the reaction.The resulting mixture was extracted with 3×200 mL of dichloromethane.The combined organic layers was washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to give 7 g (34%) oftert-butyl N-[4-(methanesulfonyloxy)cyclohexyl] carbamate as a whitesolid.

Step 3: Synthesis of methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate

A solution of methyl4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (5 g, 18.82 mmol,1.00 equiv), potassium ethanethioate (2.68 g, 23.47 mmol, 1.25 equiv)and potassium iodide (120 mg, 0.72 mmol, 0.04 equiv) in acetone (40 mL)was stirred at 35° C. for 30 min. Water (50 mL) was added to quench thereaction. The resulting solution was extracted with 3×100 mL of ethylacetate. The combined organic layers was washed with 2×200 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum togive 6.03 g of crude methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as awhite solid.

Step 4: Synthesis of methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate

A mixture of methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (4.29 g,14.05 mmol, 1.00 equiv) and potassium carbonate (4.85 g, 34.84 mmol,3.00 equiv) in methanol (50 mL) was stirred at 35° C. under an inertatmosphere of nitrogen for 30 min. Water (100 mL) was then added and theresulting solution was extracted with 3×150 mL of dichloromethane. Thecombined organic layers was washed with 2×300 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to yield 3.8 g ofcrude methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate asa white solid. LC-MS: (ES, m/z): 305 [M+CH₃CN+H]⁺, 264 [M+H]⁺, 230.

Step 5: Synthesis of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed A mixture of methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3 g, 11.39mmol, 1.00 equiv), cescium carbonate (5.13 g, 15.70 mmol, 1.39 equiv)and tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (3.22 g,10.98 mmol, 1.20 equiv) in N,N-dimethylformamide (30 mL) was stirred at50° C. for 3 h. The reaction was quenched by the addition of 50 mL ofwater and the resulting solution was extracted with 3×60 mL of ethylacetate. The organic combined layers was washed with 2×200 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified on\a silica gel column eluted with ethylacetate/petroleum ether (1:15-1:5). The collected fractions werecombined and concentrated under vacuum to give 760 mg (14%) of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoateas a yellow solid. LC-MS: (ES, m/z): 461 [M+H]⁺, 405, 361, 271, 230,115.

Step 6: Synthesis of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate

A mixture of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate(760 mg, 1.65 mmol, 1.00 equiv) and 3-chlorobenzene-1-carboperoxoic acid(1.42 g, 8.23 mmol, 2.50 equiv) in chloroform (30 mL) was stirred at 0°C. for 30 min. The resulting mixture was washed successively with 2×100mL of aqueous sodium bisulphite solution, 2×100 mL of aqueous sodiumbicarbonate solution and 2×100 mL of brine. The organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum to give 730mg (90%) of methyl 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate as a yellow solid.LC-MS: (ES, m/z): 437 [M-C₄H₈+H]⁺, 393.

Step 7: Synthesis of4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoicacid

To a solution of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate (730 mg, 1.48 mmol,1.00 equiv) in methanol (20 mL) was added a solution of sodium′hydroxide (180 mg, 4.50 mmol, 3.00 equiv) in water (5 mL). Theresulting solution was stirred at 50° C. for 2.5 h and then concentratedunder vacuum.

A mixture of ice/water (50 mL) was added and the pH value of thesolution was adjusted to 3 with 3M hydrochloric acid. The precipitatewas collected by filtration, washed with water and dried in a vacuumoven to give 0.43 g (61%) of4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoic acid as a yellowsolid. LC-MS: (ES, m/z): 479-56 [M+H]⁺

Step 8: Synthesis of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate

A solution of4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoicacid (430 mg, 0.90 mmol, 1.00 equiv), pyridin-3-ylmethanamine (120 mg,1.11 mmol, 1.20 equiv), EDC (510 mg, 3.29 mmol, 3.00 equiv),1H-1,2,3-benzotriazol-1-ol (150 mg, 1.11 mmol, 1.20 equiv) andtriethylamine (270 mg, 2.67 mmol, 3.00 equiv) in N,N-dimethylformamide(20 mL) was stirred overnight at room temperature. The reaction was thenquenched by the addition of 60 mL of water/ice. The solid was collectedby filtration, washed with water and dried in a vacuum oven to give 430mg (84%) of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate as ayellow solid. LC-MS: (ES, m/z): 569 [M+H]⁺, 513, 469, 347, 306.

Step 9: Synthesis of4-(4-(((1s,4s)-4-aminocyclohexylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidehydrochloride

Hydrogen chloride gas was bubbled into a solution of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate(430 mg, 0.76 mmol, 1.00 equiv) in dichloromethane (20 mL). Theresulting solution was stirred at 0° C. for 2 h. The resulting mixturewas concentrated under vacuum. The crude product (80 mg) was dissolvedin distilled water and dried under lyophilization conditions to give 49mg (13%) of4-(4-(((1s,4s)-4-aminocyclohexylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidehydrochloride as a white solid. LC-MS: (ES, m/z): 469 [M+H]⁺, 276, 256.H-NMR: ¹HNMR (400 MHz, CD₃OD, ppm) δ 9.41-9.39 (1H, t), 8.91 (1H, s),8.80-8.79 (1H, d), 8.65-8.63 (1H, d), 8.13-8.02 (5H, m), 4.81-4.80 (2H,s), 4.49 (2H, s), 3.41 (1H, s), 3.33 (2H, s), 2.51 (3H, s), 2.34-2.31(2H, s), 2.12-2.02 (4H, m), 1.98-1.94 (3H, s).

Example 42 Synthesis of4-[5-methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas the trifluoroacetic acid salt

A solution of4-(4-(((1S,4S)-4-aminocyclohexylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidehydrochloride (140 mg, 0.30 mmol, 1.00 equiv) (Example 3),1,4-dibromobutane (60 mg, 0.28 mmol, 1.20 equiv) and potassium carbonate(140 mg, 1.01 mmol, 4.00 equiv) in N,N-dimethylformamide (10 mL) wasstirred at 70° C. for 4 h. The reaction was quenched by the addition of30 mL of water and the resulting solution was extracted with 3×40 mL ofdichloromethane. The combined organic layers was washed with 2×100 mL ofaqueous sodium chloride solution, dried over anhydrous sodium sulfateand concentrated under vacuum. The crude product (100 mg) was purifiedby Prep-HPLC with the following conditions (2#-Waters 2767-1 (HPLC-07)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05%TFA and CH3CN (5% CH3CN up to 25% in 13 min, up to 100% in 2 min, downto 5% in 2 min); Detector, UV 220 nm to give 31.3 mg (16%) of4-[5-methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas the trifluoroacetic acid salt that was a white solid. LC-MS: (ES,m/z): 523 [M+H]⁺, 283, 262. ¹H-NMR[400 Hz, CD₃OD, ppm] δ8.90 (1H, s),8.79-8.78 (2H, d), 8.63-8.61 (1H, d), 8.13-8.11 (2H, d), 8.08-8.01 (3H,d), 4.79 (2H, s), 4.51 (2H, s), 3.66 (2H, s), 3.46-3.32 (1H, d),3.28-3.25 (1H, m), 3.18-3.11 (2H, m), 2.51 (5H, s), 2.16-1.99 (10H, m).

Example 43 Synthesis of4-[5-Methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt

A solution of4-(4-(((1S,4S)-4-aminocyclohexylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidehydrochloride (100 mg, 0.21 mmol, 1.00 equiv), 1,5-dibromopentane (40mg, 0.17 mmol, 1.20 equiv) and potassium carbonate (30 mg, 0.22 mmol,4.00 equiv) in N,N-dimethylformamide (7 mL) was stirred at 70° C. for 4h. The reaction was then quenched by the addition of 43 mL of water andthe resulting solution was extracted with 3×40 mL of dichloromethane.The combined organic layers was washed with 2×100 mL of aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedunder vacuum. The crude product (90 mg) was purified by Prep-HPLC withthe following conditions (2#-Waters 2767-1 (HPLC-07)): Column, SunFirePrep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN(5% CH3CN up to 15% in 2 min, up to 45% in 8 min, up to 100% in 1 min,down to 5% in 1 min); Detector, UV 220 nm, to yield 8.8 mg (8%) of4-[5-methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas the trifluoroacetic acid salt that was a white solid. LC-MS: (ES,m/z): 537[M+H]⁺, 290, 269. ¹H-NMR (400 Hz, CD₃OD, ppm) δ 8.59 (1H, s),8.47-8.46 (1H, d), 8.11-8.09 (2H, d), 7.99-7.97 (2H, d), 7.90-7.88 (1H,d), 7.46-7.43 (1H, m), 4.65 (2H, s), 4.43 (2H, s), 2.56 (4H, s), 2.50(4H, s), 2.39 (3H, s), 2.09-2.01 (2H, m), 1.91-1.85 (2H, m), 1.71-1.63(7H, m), 1.48 (3H, s).

Example 44 Synthesis of4-(4-[[(4-Aminocyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt Step 1: Synthesis of4-[[(tert-butoxy)carbonyl]amino]cyclohexyl acetate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (15 g,69.67 mmol, 1.00 equiv), acetic acid (16.7 g, 278.09 mmol, 4.00 equiv)and triphenylphosphane (73 g, 278.32 mmol, 4.00 equiv). intetrahydrofuran (200 mL) was added diethyl azodicarboxylate (48.55 g,278.78 mmol, 4.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred overnight at room temperature and then 200 mL ofaqueous sodium bicarbonate solution was added. The resulting mixture wasextracted with 3×100 mL of ethyl acetate. The combined organic layerswas dried over anhydrous sodium sulfate and concentrated under vacuum.The crude product was triturated with 500 mL of a 1:1 mixture of etherand hexane. The solid triphenylphosphine oxide was removed byfiltration. The filtrate was concentrated under vacuum and purified on asilica gel column eluted with ethyl acetate/petroleum ether (1:15) togive 3.8 g (21%) of 4-[[(tert-butoxy)carbonyl]amino]cyclohexyl acetateas a white solid.

Step 2: Synthesis of tert-butyl N-(4-hydroxycyclohexyl)carbamate

A mixture of 4-[[(tert-butoxy)carbonyl]amino]cyclohexyl acetate (2.43 g,9.44 mmol, 1.00 equiv), methanol (30 mL) and potassium carbonate (2 g,14.37 mmol, 1.50 equiv) was stirred overnight at 25° C. The resultingmixture was concentrated under vacuum. Water (50 mL) was added and theresulting solution was extracted with 3×70 mL of dichloromethane. Theorganic layers were combined and washed with 2×200 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum to give 2.19 g of crude tert-butylN-(4-hydroxycyclohexyl)carbamate as yellow oil.

Step 3: Synthesis of tert-butylN-[4-(methanesulfonyloxy)cyclohexyl]carbamate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (3.8 g,17.65 mmol, 1.00 equiv) and triethylamine (3.9 g, 38.54 mmol, 2.20equiv) in dichloromethane (40 mL) was added methanesulfonyl chloride(2.43 g, 21.21 mmol, 1.21 equiv) dropwise with stirring at 0° C. Thereaction mixture was stirred overnight at room temperature. Water (50mL) was added to quench the reaction. The resulting mixture wasextracted with 3×50 mL of dichloromethane. The combined organic layerswas washed with 2×200 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum to give 3.0 g (58%) of tert-butylN-[4-(methanesulfonyloxy)cyclohexyl]carbamate as a white solid.

Step 4: Synthesis of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate

A solution of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate(2.24 g, 7.64 mmol, 1.00 equiv), methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3.0 g, 11.39mmol, 1.20 equiv) and cesium carbonate (5.55 g, 16.98 mmol, 2.00 equiv)in N,N-dimethylformamide (30 mL) was stirred at 50° C. under nitrogenatmosphere for 3 h. Water (100 mL) was added to quench the reaction. Theresulting solution was extracted with 3×80 mL of ethyl acetate. Thecombined organic layers was washed with 2×200 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:15-2:1) to give 960 mg (27%) of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoateas a yellow solid. LC-MS: (ES, m/z): 461 [M+H]⁺, 405, 271, 230, 102.

Step 5: Synthesis of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate

To a solution of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate(960 mg, 2.08 mmol, 1.00 equiv) in chloroform (30 mL) was addedm-chloroperbenzoic acid (1.8 g, 10.43 mmol, 2.50 equiv) in smallportions at 0° C. The resulting solution was stirred at 0° C. for 30min. The reaction mixture was washed with 2×100 mL of aqueous sodiumbisulphite solution, 2×100 mL of aqueous sodium bicarbonate solution and2×100 mL of brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum to give 950 mg (93%) of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoateas a yellow solid. LC-MS: (ES, m/z): 437 [M-C₄H₈+H]⁺, 393, 230.

Step 6: Synthesis of4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoicacid

To a solution of methyl4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate (950 mg, 1.93 mmol,1.00 equiv) in methanol (30 mL) was added a solution of sodium hydroxide(230 mg, 5.75 mmol, 3.00 equiv) in water (5 mL). The reaction mixturewas stirred overnight at 50° C. and then concentrated under vacuum. Amixture of water/ice (60 mL) was added and the pH value of the solutionwas adjusted to 3 with 3M hydrochloric acid. The precipitate wascollected by filtration and dried in a vacuum oven to give 800 mg (87%)of 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoic acid as a white solid.LC-MS: (ES, m/z): 479 [M+H]⁺, 423, 379, 279, 141, 115.

Step 7: Synthesis of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate

To a solution of 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoic acid (800 mg, 1.67mmol, 1.00 equiv), pyridin-3-ylmethanamine (220 mg, 2.03 mmol, 1.20equiv), EDC (950 mg, 6.12 mmol, 3.00 equiv) and1H-1,2,3-benzotriazol-1-ol (270 mg, 2.00 mmol, 1.20 equiv) inN,N-dimethylformamide (20 mL) was added triethylamine (510 mg, 5.04mmol, 3.00 equiv) dropwise with stirring. The resulting solution wasstirred for 3 h at 30° C. and then quenched by the addition of 100 mL ofwater/ice. The solid was collected by filtration and dried in a vacuumoven to give 790 mg (83%) of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate as ayellow solid. LC-MS: (ES, m/z): 569 [M+H]⁺, 513, 469, 306, 115.

Step 8: Synthesis of4-(4-[[(4-aminocyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt

Hydrogen chloride gas was bubbled into a solution of tert-butylN-(4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclohexyl)carbamate(790 mg, 1.39 mmol, 1.00 equiv) in dichloromethane (30 mg, 0.35 mmol,0.25 equiv). The resulting solution was stirred for 3 h at 0° C. thenconcentrated under vacuum. The crude product (100 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH0.05% TFA and CH3CN (10.0% CH3CN up to 35.0% in 12 min, up to 100.0% in1 min); Detector, UV 254 nm. 33.1 mg product was obtained. This resultedin 33.1 mg (3%) of4-(4-[[(4-aminocyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,a white solid as the trifluoroacetic acid salt. LC-MS: (ES, m/z): 469[M+H]⁺, 297, 277. ¹H-NMR (400 MHz, CD₃OD, ppm) δ 8.89 (1H, s), 8.79-8.77(1H, d), 8.61-8.59 (1H, d), 8.13-8.11 (2H, d), 8.06-8.01 (3H, m), 4.79(2H, s), 4.44 (2H, s), 3.22-3.16 (2H, t), 2.46-2.43 (5H, d), 2.25-2.23(2H, d), 1.80-1.71 (2H, m), 1.54-1.45 (2H, m).

Example 454-[5-Methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetate

A mixture of4-(4-[[(4-aminocyclohexane)sulfonyl]methyl]-5-methyl-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideditrifluoroacetate (100 mg, 0.20 mmol, 1.00 equiv), potassium (120 mg,0.86 mmol, 4.00 equiv) and 1,4-dibromobutane (55 mg, 0.25 mmol, 1.20equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at 70° C.The reaction was then quenched by the addition of 40 mL of water andthen extracted with 3×50 mL of dichloromethane. The organic combinedlayers was washed with 2×200 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The crude product (120 mg) waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-005(Waters)): Column, Xbridge Prep C18, 5 um, 19*150 mm;mobile phase, WATER WITH 0.05% TFA and CH3CN (10.0% CH3CN up to 30.0% in12 min, up to 100.0% in 1 min); Detector, UV 254 nm, to give 34.2 mg(23%) of4-[5-methyl-4-([[4-(pyrrolidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide,a white oil as its trifluoroacetic acid salt. LC-MS: (ES, m/z):523[M+H]⁺, 283, 263. ¹H-NMR (400 MHz, CD₃OD, ppm) δ 8.90 (1H, s),8.80-8.78 (1H, d), 8.63-8.61 (1H, d), 8.14-8.11 (2H, d), 8.08-8.01 (3H,t), 4.80 (2H, s), 4.45 (2H, s), 3.66 (2H, s), 2.47-2.40 (7H, m), 2.17(2H, s), 2.03-2.00 (2H, d), 1.77-1.71 (2H, m), 1.62-1.57 (2H, m).

Example 464-[5-Methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A mixture of4-(4-((trans-4-aminocyclohexylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidebistrifluoroacetate (170 mg, 0.33 mmol, 1.00 equiv), potassium carbonate(200 mg, 1.44 mmol, 4.00 equiv), 1,5-dibromopentane (99 mg, 0.43 mmol,1.20 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at70° C. Water (40 mL) was added and the resulting solution was extractedwith 3×50 mL of dichloromethane. The combined organic layers was washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product (120 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-005(Waters)): Column, SunFire PrepC18, 5 um, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and CH3CN(17.0% CH3CN up to 40.0% in 12 min, up to 100.0% in 1 min); Detector, UV254/220 nm, to yield 12.6 mg (7%) of4-[5-methyl-4-([[4-(piperidin-1-yl)cyclohexane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 537 [M+H]⁺, 290, 263. ¹H-NMR (400MHz, CD₃OD, ppm) δ 8.59 (1H, s), 8.47-8.46 (1H, d), 8.12-8.10 (2H, d),8.00-7.98 (2H, d), 7.90-7.88 (1H, d), 7.46-7.43 (1H, t), 4.65 (2H, s),4.40 (2H, s), 3.14-3.07 (1H, m), 2.62 (4H, s), 2.50 (3H, s), 2.41-2.38(3H, d), 2.16-2.13 (2H, d), 1.70-1.64 (6H, m), 1.49-1.37 (4H, m).

Example 47 Synthesis of4-[4-([[(1S,3S)-3-Aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidebis-trifluoroacetic acid salt Step 1: Synthesis of tert-butylN-hydroxycarbamate

To a mixture of di-tert-butyl dicarbonate (12 g, 54.98 mmol, 0.33 equiv)and aqueous sodium carbonate solution (w/w=0.176) (117.6 g) intetrahydrofuran (100 mL) was added a solution of hydroxylaminehydrochloride (11.6 g, 166.93 mmol, 1.00 equiv) in water (100 mL)dropwise with stirring at room temperature. The resulting solution wasstirred overnight at room temperature. Water (100 mL) was added and themixture was extracted with 3×150 mL of ethyl acetate. The combinedorganic layers was dried over anhydrous sodium sulfate and concentratedunder vacuum to give 15 g (67%) of tert-butyl N-hydroxycarbamate as awhite solid.

Step 2: Synthesis of tert-butyl2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

To a solution of tert-butyl N-hydroxycarbamate (9.2 g, 69.10 mmol, 1.00equiv) and cyclopenta-1,3-diene (20.2 g, 305.59 mmol, 4.42 equiv) inmethanol (600 mL) was added of a solution of sodium periodate (17 g,79.48 mmol, 1.15 equiv) in water (180 mL) dropwise at 0° C. withstirring in 30 min. The reaction mixture was stirred for another 30 minat 0° C. and then diluted with 600 mL of water. The solution wasextracted with 3×300 mL of ethyl acetate. The combined organic layerswas washed with 2×200 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum to give 9.1 g (67%) of tert-butyl2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate as a white solid.¹HNMR (400 MHz, D₂O, ppm) δ 6.42 (2H, s), 5.22 (1H, s), 4.99 (1H, s),1.99 (1H, d, J=8.4 Hz), 1.73 (1H, d, J=8.4 Hz), 1.47 (9H, s).

Step 3: Synthesis of tert-butylN-[(1S,3R)-3-hydroxycyclopentyl]carbamate

A mixture of tert-butyl2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (8.0 g, 40.56 mmol,1.00 equiv) and palladium on carbon (0.5 g) catalyst in methanol (100mL) was stirred under an atmosphere of hydrogen atmosphere at 60° C. for48 h. The reaction mixture was cooled to room temperature and thecatalyst was removed by filtration. The catalyst was washed with 3×10 mLof MeOH. The combined filtrate and washings was concentrated undervacuum to give 6.5 g (80%) of tert-butylN-[(1S,3R)-3-hydroxycyclopentyl]carbamate as a white solid. ¹HNMR (400MHz, D₂O, ppm) δ 4.72 (1H, s), 4.55 (1H, s), 1.92-1.87 (3H, m),1.76-1.60 (3H, m), 1.50 (9H, s).

Step 4: Synthesis of tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate

To a solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate(3.0 g, 14.91 mmol, 1.00 equiv) and triethylamine (3.0 g, 29.65 mmol,1.99 equiv) in dichloromethane (50 mL) was added methanesulfonylchloride (2.2 g, 19.21 mmol, 1.29 equiv) dropwise with stirring at 0-5°C. After addition was completed, the reaction mixture was warmed to roomtemperature and stirred at room temperature for 2 h. The mixture wasdiluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate.The combined organic layers was washed with 2×30 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to give 3.8 g(91%) of tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate as a white solid.

Step 5: Synthesis of methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate

A solution of methyl4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (10 g, 37.64 mmol,1.00 equiv), potassium ethanethioate (5 g, 43.78 mmol, 1.16 equiv) andpotassium iodide (300 mg, 1.81 mmol, 0.05 equiv) in acetone (160 mL) wasstirred at 35° C. under nitrogen for 30 min. The product wasprecipitated by the addition of 250 mL water. The precipitate wascollected by filtration, washed with water and dried in a vacuum oven togive 10.5 g (91%) of methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as awhite solid.

Step 6: Synthesis of methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate

A mixture of methyl4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (10.5 g,34.39 mmol, 1.00 equiv) and potassium carbonate (12.3 g, 89.00 mmol,2.59 equiv) in methanol (200 mL) was stirred at 35° C. under an inertatmosphere of nitrogen for 30 min. Water (200 mL) was added and theresulting solution was extracted with 3×100 mL of dichloromethane. Thecombined organic layers was washed with 3×50 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. To afford 8.4 g(93%) of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoateas a white solid. LC-MS-: (ES, m/z): 305 [M+CH₃CN+H]⁺, 264 [M+H]⁺, 230.

Step 7: Synthesis of methyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate

To a solution of methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (920 mg, 3.49mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under aninert atmosphere of nitrogen was added cescium camonate (2.3 g). Themixture was stirred for 20 min then tert-butylN-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (1.0 g, 3.58mmol, 1.02 equiv) was added. The resulting solution was stirred at 35°C. for 50 min then the product was precipitated by the addition of 50 mLwater. The precipitate was collected by filtration, washed with waterand then dried under vacuum to give 1.37 g (88%) of methyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoateas a white solid. LC-MS: (ES, m/z): 447 [M+H]⁺, 391, 271, 230, 115.

Step 8: Synthesis of methyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate

To a solution of methyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate(1.3 g, 2.91 mmol, 1.00 equiv) in chloroform (30 mL) maintained undernitrogen at 0-5° C. was added m-chloroperbenzoic acid (1.25 g, 7.24mmol, 2.49 equiv) in several batches. The resulting solution was stirredfor 2 h at 0-5° C. then quenched by the addition of saturated aqueoussodium bisulphite solution (20 mL) and aqueous sodium carbonate solution(20 mL). The resulting mixture was extracted with 60 mL of chloroform.The organic layer was washed with 3×20 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum to give 1.28 g (92%) ofmethyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoateas a white solid. LC-MS: (ES, m/z): 479 [M+H]⁺, 423.

Step 9: Synthesis of4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoicacid

To a solution of methyl4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate(1.28 g, 2.67 mmol, 1.00 equiv) in methanol (30 mL) was added a solutionof sodium hydroxide (640 mg, 16.00 mmol, 5.98 equiv) in water (6 mL).The resulting solution was stirred at 50° C. for 2 h. The pH value ofthe solution was adjusted to 2-3 with 2N hydrochloric acid. Theprecipitate was collected by filtration, washed with 3×20 mL of waterand dried in a vacuum oven to give 1.1 g (89%) of4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoicacid as a white solid. LC-MS: (ES, m/z): 465 [M+H]⁺, 409.

Step 10: Synthesis of tert-butylN-[(1S,3S)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamate

A solution of4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoicacid (1.1 g, 2.37 mmol, 1.00 equiv), EDCI (600 mg, 3.13 mmol, 1.32equiv), HOBt (420 mg, 3.11 mmol, 1.31 equiv), triethylamine (720 mg,7.12 mmol, 3.00 equiv) and pyridin-3-ylmethanamine (500 mg, 4.62 mmol,1.95 equiv) in N,N-dimethylformamide (30 mL) was stirred at 35° C.overnight. The product was precipitated by the addition of 80 mL water.The precipitate was collected by filtration, washed with water and driedunder vacuum to give 1.0 g (76%) of tert-butylN-[(1S,3S)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamateas a white solid. LC-MS: (ES, m/z): 555 [M+H]⁺, 499, 306, 264.

Step 11: Synthesis of4-[4-([[(1S,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidebis-trifluoroacetic acid salt

Hydrogen chloride gas was bubbled into a solution of tert-butylN-[(1S,3S)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamate(1.0 g, 1.80 mmol, 1.00 equiv) in dichloromethane (20 mL). The resultingsolution was stirred for 2 h at 0-5° C. then concentrated under vacuum.The crude product (300 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-005(Waters)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (5% CH3CN up to25% in 12 min, up to 100% in 1 min); Detector, uv 254 nm, to give 200 mg(16%) of4-[4-([[(1S,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidebis-trifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 455[M+H]⁺, 290, 245. ¹HNMR (400 MHz, D₂O ppm) δ 8.66 (1H, s), 8.59 (H, d,J=5.6 Hz), 8.47 (1H, d, J=8.0 Hz), 7.94-7.91 (1H, m), 7.85 (2H, d, J=8.4Hz), 7.73 (2H, d, J=8.4 Hz), 4.65 (2H, s), 4.37 (2H, s), 3.92-3.84 (1H,m), 3.73-3.69 (1H, m), 2.52-2.45 (1H, m), 2.28 (3H, s), 2.24-2.18 (2H,m), 2.12-2.03 (2H, m), 1.73-1.68 (1H, m).

Example 48 Synthesis of4-[5-Methyl-4-([[(1S,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A solution of4-[4-([[(1S,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetic acid (350 mg, 0.72 mmol, 1.00 equiv), 1,4-dibromobutane(180 mg, 0.84 mmol, 1.18 equiv) and potassium carbonate (250 mg, 1.81mmol, 2.53 equiv) in N,N-dimethylformamide (20 mL) was stirred overnightat 70° C. The resulting solution was diluted with 60 mL of water thenextracted with 2×30 mL of ethyl acetate. The combined organic layers waswashed with 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product (300 mg) was purified byPrep-HPLC with the following conditions (2#-Waters 2767-2 (HPLC-08)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, Water with 50mmolNH4HCO3 and CH3CN (10.0% CH3CN up to 25.0% in 2 min, up to 40.0% in8 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, UV 254nm, to yield 50 mg (14%) of4-[5-methyl-4-([[(1S,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 509 [M+H]⁺, 296, 275. ¹H-NMR: (400MHz, CD₃OD, ppm) δ 8.60 (1H, s), 8.46 (1H, d, J=4.8 Hz), 8.12-8.10 (2H,m), 7.98 (2H, d, J=8.4 Hz), 7.88 (1H, d, J=7.6 Hz), 7.46-7.43 (1H, m),4.65 (2H, s), 4.40 (2H, s), 3.86-3.78 (1H, m), 2.81-2.74 (1H, m), 2.62(4H, s), 2.50 (3H, s), 2.40-2.23 (2H, m), 2.13-2.00 (3H, m), 1.83 (4H,s), 1.69-1.59 (1H, m).

Example 49 Synthesis of4-[5-Methyl-4-([[(1S,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidebis-trifluoroacetic acid salt

A solution of4-[4-([[(1S,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetate (350 mg, 0.72 mmol, 1.00 equiv), 1,5-dibromopentane(200 mg, 0.88 mmol, 1.23 equiv) and potassium carbonate (300 mg, 2.17mmol, 3.04 equiv) in N,N-dimethylformamide (20 mL) was stirred overnightat 70° C. The reaction mixture was diluted with 60 mL of water thenextracted with 2×30 mL of ethyl acetate. The combined organic layers waswashed with 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product (300 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05%TFA and CH3CN (5.0% CH3CN up to 25.0% in 12 min, up to 100.0% in 1 min);Detector, UV 254/220 nm, to give 60 mg (11%) of4-[5-methyl-4-([[(1S,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidebis-trifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 523[M+H]⁺, 263. ¹H-NMR: (400 MHz, D₂O, ppm) δ 8.70 (1H, s), 8.61 (1H, d,J=5.6 Hz), 8.50 (1H, d, J=8.0 Hz), 7.96 (3H, d, J=7.2 Hz), 7.81 (2H, d,J=8.0 Hz), 4.70 (2H, s), 4.44 (2H, s), 3.91-3.90 (1H, m), 3.63-3.44 (3H,m), 2.89-2.85 (2H, m), 2.59-2.58 (1H, m), 2.35 (3H, s), 2.32-2.15 (3H,m), 2.05-1.99 (1H, m), 1.85-1.53 (7H, m).

Example 50 Synthesis of4-[4-([[(1R,3S)-3-Aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidehydrochloride Step 1: Synthesis of tert-butylN-[(1S,3S)-3-iodocyclopentyl]carbamate

A solution of tert-butylN-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (2.1 g, 7.52mmol, 1.00 equiv) and sodium iodide (7 g, 46.70 mmol, 6.21 equiv) inacetone (40 mL) was stirred at 50° C. for 30 min. The reaction mixturewas diluted with 100 mL of water then extracted with 2×30 mL of ethylacetate. The combined organic layers was washed with 2×50 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified on a silica gel column with ethyl acetate/petroleumether (1/5) to give 1.0 g (43%) of tert-butylN-[(1S,3S)-3-iodocyclopentyl]carbamate as a white solid.

Step 2: Synthesis of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate

To a solution of methyl4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (870 mg, 3.30mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under anatmosphere of nitrogen at 35° C. was added cesium carbonate (2.5 g, 7.65mmol, 2.32 equiv). After stirring at 35° C. for 20 min, tert-butylN-[(1S,3S)-3-iodocyclopentyl]carbamate (1.25 g, 4.02 mmol, 1.22 equiv)was then added. The resulting solution was allowed to stir for 50 min at35° C. under nitrogen after which the product was precipitated by theaddition of 50 mL water. The solid was collected by filtration, washedwith water then dried in a vacuum oven to give 1.35 g (91%) of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoateas a white solid.

Step 3: Synthesis of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate

To a solution of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate(1.3 g, 2.91 mmol, 1.00 equiv) in chloroform (50 mL) at 0-5° C. wasadded m-chloroperbenzoic acid (1.25 g, 7.24 mmol, 2.49 equiv) in severalbatches. The resulting solution was stirred at 0˜5° C. for 2 h.Saturated aqueous sodium bisulphite solution (20 mL) and saturatedsodium carbonate solution (20 mL) were added to quench the reaction. Theresulting solution was extracted with 2×30 mL of chloroform. Thecombined organic layers was washed with 3×20 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to give 1.2 g(86%) of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoateas a white solid.

Step 4: Synthesis of4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid

To a solution of methyl4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate(1.2 g, 2.51 mmol, 1.00 equiv) in methanol (30 mL) was added a solutionof sodium hydroxide (640 mg, 16.00 mmol, 6.38 equiv) in water (6 mL).The resulting solution was stirred at 50° C. for 2 h. The product wasprecipitated by adjusting the pH of the solution to 2-3 with 2Nhydrochloric acid. The solid was collected by filtration, washed with3×20 mL of water and dried in an oven to give 1.0 g (86%) of4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoicacid as a white solid.

Step 5: Synthesis of tert-butylN-[(1S,3R)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamate

A solution of4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoicacid (1.0 g, 2.15 mmol, 1.00 equiv), EDCI (540 mg, 2.82 mmol, 1.31equiv), HOBt (380 mg, 2.81 mmol, 1.31 equiv), triethylamine (650 mg,6.42 mmol, 2.98 equiv) and pyridin-3-ylmethanamine (300 mg, 2.77 mmol,1.29 equiv) in N,N-dimethylformamide (30 mL) was stirred overnight at35° C. The product was precipitated by the addition of 80 mL water. Thesolid was collected by filtration, washed with 2×30 mL of water anddried in a vacuum oven to give 1.0 g (84%) of tert-butylN-[(1S,3R)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamateas a white solid.

Step 6: Synthesis of4-[4-([[(1R,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidehydrochloride

Excess hydrogen chloride gas was bubbled into a solution of tert-butylN-[(1S,3R)-3-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]cyclopentyl]carbamate(1.0 g, 1.81 mmol, 1.00 equiv) in dichloromethane (20 mL) at 0-5° C. Themixture was stirred at 0-5° C. for 2 h then concentrated under vacuum togive 0.9 g of a white solid. The crude product was purified by Prep-HPLCwith the following conditions (1#-Pre-HPLC-005(Waters)): Column, XbridgePrep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 50 mLNH4CO3 andCH3CN (7.0% CH3CN up to 17.0% in 2 min, up to 32.0% in 8 min, up to100.0% in 1 min); Detector, uv 254/220 nm, to give 450 mg (51%) of4-[4-([[(1R,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidehydrochloride as a white solid. LC-MS: (ES, m/z): 455 [M+H]⁺, 249, 228.¹H-NMR (400 MHz, CD₃OD, ppm) δ 8.59 (1H, s), 8.48-8.46 (1H, m),8.13-8.10 (2H, m), 7.98 (2H, d, J=8.4 Hz), 7.88 (1H, d, J=8.0 Hz),7.47-7.43 (1H, m), 4.65 (2H, s), 4.40 (2H, s) 3.77-3.73 (1H, m),3.43-3.33 (1H, m), 2.50 (3H, s), 2.48-2.25 (2H, m), 2.16-1.87 (3H, m),1.67-1.62 (1H, m).

Example 51 Synthesis of4-[5-Methyl-4-([[(1R,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A mixture of4-[4-([[(1R,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidehydrochloride (300 mg, 0.61 mmol, 1.00 equiv), potassium carbonate (250mg, 1.81 mmol, 2.95 equiv) and 1,4-dibromobutane (160 mg, 0.75 mmol,1.22 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at70° C. The reaction mixture was diluted with 60 mL of water thenextracted with 2×30 mL of ethyl acetate. The combined organic layers waswashed with 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product (300 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 50mLNH4CO3 and CH3CN (17.0% CH3CN up to 35.0% in 12 min, up to 100.0% in 1min); Detector, UV 254/220 nm, to give 30 mg (10%) of4-[5-methyl-4-([[(1R,3S)-3-(pyrrolidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 509 [M+H]⁺, 275. ¹H-NMR: (400 MHz,CD₃OD, ppm) δ 8.59 (1H, s), 8.46 (1H, d, J=4.0 Hz), 8.10 (2H, d, J=8.4Hz), 7.98 (2H, d, J=8.4 Hz), 7.88 (1H, d, J=7.6 Hz), 7.46-7.43 (1H, m),4.69 (2H, s), 4.39 (2H, s), 3.76-3.73 (1H, m), 2.72-2.64 (5H, m),2.50-2.43 (4H, m), 2.28-2.25 (1H, m), 2.12-1.96 (4H, m), 1.83 (4H, s),1.73-1.67 (1H, m).

Example 52 Synthesis of4-[5-Methyl-4-([[(1R,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A mixture of4-[4-([[(1R,3S)-3-aminocyclopentane]sulfonyl]methyl)-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidehydrochloride (300 mg, 0.61 mmol, 1.00 equiv), potassium carbonate (250mg, 1.81 mmol, 2.95 equiv) and 1,5-dibromopentane (170 mg, 0.75 mmol,1.22 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at70° C. Water (60 mL) was then added and the resulting solution wasextracted with 2×30 mL of ethyl acetate. The combined organic layers waswashed with 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product (310 mg) was purified byPrep-HPLC with the following conditions (2#-Waters 2767-1 (HPLC-07)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 50mLNH4CO3 and CH3CN (17.0% CH3CN up to 40.0% in 16 min, up to 100.0% in 1min); Detector, UV 254 nm, to give 50 mg (16%) of4-[5-methyl-4-([[(1R,3S)-3-(piperidin-1-yl)cyclopentane]sulfonyl]methyl)-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 523 [M+H]⁺, 283. ¹H-NMR: (400 MHz,CD₃OD, ppm) δ 8.59 (1H, s), 8.46 (1H, d, J=4.4 Hz), 8.10 (2H, d, J=8.4Hz), 7.98 (2H, d, J=8.4 Hz), 7.88 (1H, d, J=8.0 Hz), 7.46-7.43 (1H, m),4.65 (2H, s), 4.40 (2H, s), 3.76-3.68 (1H, m), 2.79 (1H, s), 2.58-2.44(8H, m), 2.28-2.21 (1H, m), 2.10-2.02 (2H, m), 1.98-1.90 (1H, m),1.71-1.63 (5H, m), 1.50 (2H, s).

Example 53 Synthesis of4-(5-methyl-4-[[1-(2-methylpropyl)piperidine-4-sulfonyl]methyl]-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

A solution of4-[5-methyl-4-[piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide(300 mg, 0.66 mmol, 1.00 equiv), acetic acid (59.3 mg, 0.99 mmol, 1.50equiv) and 2-methylpropanal (57 mg, 0.79 mmol, 1.20 equiv) in1,2-dichloroethane (3 mL) was stirred at room temperature for 4 h.Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was addedin small batches and the resulting solution was stirred overnight at 30°C. The resulting mixture was concentrated under vacuum and the residuewas diluted with 2 mL of methanol. The solution was loaded onto a C18column and eluted with acetonitrile/water to give 200 mg (59%) of4-(5-methyl-4-[[1-(2-methylpropyl)piperidine-4-sulfonyl]methyl]-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid. LC-MS (ES, m/z): 511 [M+H]⁺, 306, 256; ¹HNMR (300 MHz,CD3OD, ppm) δ □8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H),7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.41 (s, 2H), 3.33-3.08(m, 3H), 2.50.

Example 54 Synthesis of4-[4-[(1-cyclopentylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A solution of4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide(300 mg, 0.66 mmol, 1.00 equiv), cyclopentanone (84 mg, 1.00 mmol, 1.51equiv) and acetic acid (60 mg, 1.00 mmol, 1.51 equiv) in1,2-dichloroethane (10 mL) was stirred at room temperature for 4 h.Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was addedand the resulting solution was stirred overnight at room temperature.The resulting mixture was concentrated under vacuum and the residue waseluted with water/acetonitrile (95:5-20:80) on a C18 column to give 240mg (70%) of4-[4-[(1-cyclopentylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a colorless solid. LC-MS- (ES, m/z): 523 [M+H]⁺, 262; ¹HNMR (400 MHz,CD3OD, ppm) δ □8.60 (s, 1H), 8.48 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H),7.89 (d, 1H), 7.45 (m, 1H), 4.65 (s, 2H), 4.46 (s, 2H), 3.49 (d, 2H),3.37 (t, 1H), 3.02 (t, 1H), 2.58-2.55 (m, 2H), 2.51 (s, 3H), 2.37 (d,2H), 2.06-1.96 (m, 4H), 1.83-1.70 (m, 2H), 1.69-1.51 (m, 4H).

Example 55 Synthesis of4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide

A solution of4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide(300 mg, 0.66 mmol, 1.00 equiv), cyclohexanone (98 mg, 1.00 mmol, 1.51equiv) and acetic acid (120 mg, 2.00 mmol, 3.03 equiv) in1,2-dichloroethane (10 mL) was stirred for 4 h at room temperature. Tothis was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00equiv). The resulting solution was stirred overnight at room temperatureand then concentrated under vacuum. The residue was purified on a silicagel column with water/acetonitrile (95/5-20/80) to give 350 mg (99%) of4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamideas a white solid. LC-MS (ES, m/z): 537 [M+H]⁺; ¹HNMR (300 MHz, CD₃OD,ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 8.00 (d, 2H), 7.89 (d,1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.40 (s, 2H), 3.14 (d, 3H), 2.50(d, 3H), 2.41-2.33 (m, 3H), 2.25 (d, 2H), 1.92-1.83 (m, 6H), 1.67 (d,1H), 1.29-1.09 (m, 5H).

Example 56 Synthesis of4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of methyl4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate

A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6g, 22.64 mmol, 1.00 equiv), 4-methylbenzenethiol (4.2 g, 33.87 mmol) andcesium carbonate (8.8 g, 26.99 mmol, 1.19 equiv) inN,N-dimethylformamide (120 mL) was stirred under nitrogen overnight at50° C. The reaction mixture was diluted with 100 mL of water andextracted with 3×150 mL of ethyl acetate. The combined organic layerswas washed with 3×50 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was triturated with 2×50 mLof hexane. The solid was collected by filtration and dried in vacuum toyield 6.2 g (78%) of methyl4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate as a yellow solid.LC-MS: (ES, m/z): 395 [M+CH₃CN+H]⁺, 354 [M+H]⁺, 271, 203, 126, 120.

Step 2: Synthesis of4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid

A mixture of methyl4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate (3.1 g, 8.78 mmol,1.00 equiv) in 6N hydrochloric acid (90 mL) was stirred overnight at 90°C. The reaction mixture was diluted with 150 mL of water and extractedwith 3×150 mL of ethyl acetate. The combined organic layers was washedwith 3×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to give 2.2 g (74%) of4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid as a whitesolid. LC-MS: (ES, m/z):

381 [M+CH₃CN+H]⁺, 340 [M+H]⁺, 257, 216, 189, 146, 105. H-NMR: ¹HNMR (400MHz, CDCl₃, ppm) δ 8.18-8.09 (dd, 4H), 7.30-7.28 (d, 2H), 7.10-7.08 (d,2H), 3.95 (s, 2H), 2.32 (s, 3H), 2.08 (s, 3H).

Step 3: Synthesis of4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

A solution of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid(500 mg, 1.47 mmol, 1.00 equiv), EDCI (340 mg, 1.78 mmol, 1.21 equiv),1H-1,2,3-benzotriazol-1-ol (240 mg, 1.78 mmol, 1.21 equiv),pyridin-3-ylmethanamine (190 mg, 1.76 mmol, 1.19 equiv) andtriethylamine (450 mg, 4.46 mmol, 3.02 equiv) in N,N-dimethylformamide(10 mL) was stirred overnight at room temperature. The resultingsolution was diluted with 20 mL of an ice/water mixture. The precipitatewas collected by filtration, washed with 3×10 mL of hexane and 4×10 mLof 66% aqueous methanol to give 0.33 g (52%) of4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 471

[M+CH₃CN+H]⁺, 430 [M+H]⁺, 347, 306. ¹HNMR (400 MHz, DMSO-d6, ppm) δ9.22-9.20 (s, 1H), 8.57 (s, 1H), 8.46 (d, 1H), 8.02-7.97 (t, 4H),7.75-7.73 (d, 1H), 7.38-7.35 (t, 1H), 7.30-7.28 (d, 2H), 7.14-7.13 (d,2H), 4.52-4.51 (d, 2H), 4.07 (s, 2H), 2.27 (s, 3H), 2.17 (s, 3H).

Example 57 Synthesis of4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of methyl4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate

A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(3.1 g, 11.70 mmol, 1.00 equiv), p-cresol (2.0 g, 18.52 mmol, 1.58equiv), Cs2CO3 (4.5 g, 13.80 mmol, 1.18 equiv) in N,N-dimethylformamide(60 mL) was stirred under nitrogen overnight at 50° C. The resultingsolution was diluted with 100 mL of water and extracted with 3×100 mL ofethyl acetate. The combined organic layers was washed with 3×50 mL ofbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto give 3.7 g (94%) of methyl4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate as a yellow solid.LC-MS: (ES, m/z): 379 [M+CH₃CN+H]⁺, 338 [M+H]⁺, 271, 230, 203, 146, 91.

Step 2: Synthesis of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoicacid

A mixture of methyl 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate(1.0 g, 2.97 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) wasstirred overnight at 90° C. The reaction mixture was diluted with 50 mLof water then extracted with 3×150 mL of ethyl acetate. The combinedorganic layers was washed with 3×50 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum to give 0.24 g (25%) of4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid as a graysolid. LC-MS: (ES, m/z): 324 [M+H]⁺, 302, 265, 120. H-NMR: ¹HNMR (400MHz, CDCl₃, ppm) δ 8.15-8.13 (d, 2H), 8.06-8.04 (d, 2H), 6.94-6.91 (m,4H), 3.79 (s, 2H), 2.44 (s, 3H,), 2.26 (s, 3H).

Step 3: Synthesis of4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

A solution of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid(460 mg, 1.42 mmol, 1.00 equiv), EDCI (320 mg, 1.68 mmol, 1.18 equiv),HOBT (240 mg, 1.78 mmol, 1.25 equiv), pyridin-3-ylmethanamine (180 mg,1.67 mmol, 1.17 equiv) and triethylamine (440 mg, 4.36 mmol, 3.06 equiv)in N,N-dimethylformamide (6 mL) was stirred overnight at roomtemperature. The resulting solution was diluted with 20 mL of ice/water.The solid was collected by filtration and washed with 3×10 mL of hexane.The crude product was purified on a silica gel column eluted withchloroform/methanol (50:1-20:1) to give 0.33 g (56%) of4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a gray solid. LC-MS: (ES, m/z): 414 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6,ppm) δ 9.16 (s, 2H), 8.56 (s, 1H), 8.46 (s, 1H), 8.00-7.95 (m, 3H), 7.75(d, 1H), 7.34 (m, 1H), 6.86-6.81 (m, 2H), 6.68 (d, 1H), 4.50 (d, 2H),3.78 (s, 2H), 2.50 (s, 3H), 2.14 (s, 3H).

Example 58 Synthesis of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt Step 1: Synthesis of(4-bromophenyl)-N,N-dimethylmethanamine

A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33%) andpotassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200mL) was stirred overnight at 50° C. The solid material was removed byfiltration and the filtrate was concentrated under vacuum. The residuewas dissolved in 200 mL of water and extracted with 3×200 mL ofdichloromethane. The combined organic layer was washed with 3×200 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified on a silica gel column eluted withdichloromethane/methanol (20:1) to give 10 g (58%) of(4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES,m/z): 255 [M+CH₃CN+H]⁺, 214 [M+H]⁺, 169.

Step 2: Synthesis of lithium 4-((dimethylamino)methyl)benzenesulfinate

To a solution of (4-bromophenyl)-N,N-dimethylmethanamine (4.26 g, 20.00mmol, 1.00 equiv) in tetrahydrofuran (60 mL) maintained under nitrogenat −78° C. was added in 30 min a 2.5M solution of n-butyllithium (8.8mL, 1.10 equiv) in hexane dropwise with stirring. The resulting solutionwas stirred at −78° C. for 2 h. Sulfur dioxide gas was then bubbled intothe solution at −78° C. for 1 h. Ether (200 mL) was added and theprecipitate was collected by filtration. The solid was washed with etherand dried in vacuum to give 4 g (98%) of lithium4-((dimethylamino)methyl)benzenesulfinate as a yellow solid.

Step 3: Synthesis of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoate

A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(2.65 g, 10.00 mmol, 1.00 equiv), lithium4-((dimethylamino)methyl)benzenesulfinate (3.075 g, 15.00 mmol, 1.50equiv) and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) inN,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water(150 mL) was added and the resulting solution was extracted with 3×200mL of ethyl acetate. The combined organic layers was washed with 3×200mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum to yield 0.9 g (16%) of methyl4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoateas a light yellow solid. LC-MS: (ES, m/z): 429 [M+H]⁺, 175, 120.

Step 4: Synthesis of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid hydrochloride

A solution of methyl4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoate(900 mg, 1.56 mmol, 1.00 equiv, 74%) in 6N hydrochloric acid (25 mL) wasrefluxed overnight. The resulting solution cooled to room temperatureand then diluted with 30 mL of water/ice. The solid was removed byfiltration out and washed with 3×20 mL of water. The filtrate andwashings were combined and concentrated in vacuum to give 0.6 g (84%) of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid hydrochloride as a yellow solid. LC-MS: (ES, m/z): 415 [M+H]⁺, 395,120.

Step 5: Synthesis of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt

To a solution of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid hydrochloride (540 mg, 1.20 mmol, 1.00 equiv),pyridin-3-ylmethanamine (155.52 mg, 1.44 mmol, 1.20 equiv), HOBt (194.4mg, 1.44 mmol, 1.20 equiv) and EDCI (275 mg, 1.44 mmol, 1.20 equiv) inN,N-dimethylformamide (10 mL) was added triethylamine (363.6 mg, 3.60mmol, 3.01 equiv) dropwise with stirring. The reaction mixture wasstirred overnight at room temperature and then diluted with 20 mL ofice-water. The resulting solution was extracted with 3×100 mL of ethylacetate. The combined organic layers was washed with 3×100 mL of brine,dried over anhydrous sodium sulphate and concentrated under vacuum. Thecrude product (350 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-005(Waters)): Column, Atlantis T3, 5 um, 19*150mm; mobile phase, WATER WITH 0.05% TFA and CH₃CN (10% CH₃CN up to 30% in12 min, up to 100% in 1 min); Detector, uv 254/220 nm, to give 159 mg(21%) of4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt as a yellow solid. LC-MS: (ES, m/z): 505[M+H]⁺, 274, 253. ¹HNMR (400 MHz, CD₃OD, ppm) δ 8.84 (s, 1H), 8.73 (s,1H), 8.50-8.48 (d, 1H), 7.99-7.97 (d, 7H), 7.76-7.74 (d, 2H), 4.77 (s,2H), 4.60 (s, 2H), 4.44 (s, 2H), 2.87 (s, 6H), 2.31 (s, 3H).

Example 59 Synthesis of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideTFA salt Step 1: Synthesis of lithium4-(piperidin-1-ylmethyl)benzenesulfinate

To a solution of 1-(4-bromobenzyl)piperidine (5 g, 19.76 mmol, 1.00equiv) in tetrahydrofuran (50 mL) maintained under nitrogen at −78° C.was added in 30 min a 2.5M solution of n-butyllithium (8.7 mL, 1.10equiv) in hexane dropwise with stirring. The resulting solution wasstirred at −78° C. for 2 h. Sulfur dioxide gas was then bubbled into thesolution at −78° C. for 1 h. Sulfur dioxide gas was then bubbled intothe solution at −78° C. for 1 h. Ether (200 mL) was added and theprecipitate was collected by filtration. The solid was washed with etherand dried in vacuum to give 4.8 g (99%) of lithium4-(piperidin-1-ylmethyl)benzenesulfinate as a yellow solid.

Step 2: Synthesis of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate

A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(2.65 g, 10.00 mmol, 1.00 equiv), lithium4-(piperidin-1-ylmethyl)benzenesulfinate (4.8 g, 19.59 mmol, 2.00 equiv)and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) inN,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water(150 mL) was added and the resulting solution was extracted with 3×200mL of ethyl acetate. The combined organic layers was washed with 3×200mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum to yield 4 g (53%) of methyl4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoateas a yellow solid. LC-MS: (ES, m/z): 510 [M+CH₃CN+H]⁺, 469 [M+H]⁺, 120.

Step 3: Synthesis of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride

A solution of methyl4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate(2 g, 2.65 mmol, 1.00 equiv, 62%) in 6N hydrochloric acid (50 mL) wasrefluxed overnight. The resulting mixture was concentrated under vacuumand the residue was washed with 20 mL of ethyl acetate and 20 mL ofether. The solid was dried in a vacuum oven to give 1.2 g (68%) of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride as an off-white solid. LC-MS: (ES, m/z): 496[M+CH₃CN+H]⁺, 455 [M+H]⁺

Step 4: Synthesis of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideTFA salt

To a solution of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride (1.02 g, 1.54 mmol, 1.00 equiv, 74%),pyridin-3-ylmethanamine (199.8 mg, 1.85 mmol, 1.20 equiv), HOBt (249.8mg, 1.85 mmol, 1.20 equiv) and EDCI (353.4 mg, 1.85 mmol, 1.20 equiv) inN,N-dimethylformamide (10 mL) was added triethylamine (467.2 mg, 4.63mmol, 3.00 equiv) dropwise with stirring. The reaction mixture wasstirred overnight at room temperature and then diluted with 20 mL ofice-water. The solid was collected by filtration. The crude product (350mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-005(Waters)): Column, SunFire Prep C18, 5 um, 19*150 mm;mobile phase, WATER WITH 0.05% TFA and CH₃CN (10% CH₃CN up to 30% in 12min, up to 100% in 1 min); Detector, uv 254/220 nm, to give 161.1 mg(16%) of4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideTFA salt as an off-white solid. LC-MS: (ES, m/z): 545 [M+H]⁺, 294, 273,192. ¹HNMR (400 MHz, CD₃OD, ppm) δ 8.83 (s, 1H), 8.72-8.71 (d, 1H),8.46-8.44 (d, 1H), 8.01-7.91 (m, 7H), 7.76-7.75 (d, 2H), 4.76 (s, 2H),4.60 (s, 2H), 4.42 (s, 2H), 3.45-3.42 (d, 2H), 3.02-2.99 (d, 2H), 2.32(s, 3H), 1.96-1.73 (m, 5H), 1.52 (s, 1H)

Example 60 Synthesis of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of lithium 4-(morpholinomethyl)benzenesulfinate

To a solution of 4-(4-bromobenzyl)morpholine (5.0 g, 19.61 mmol, 1.00equiv) in tetrahydrofuran (60 mL) maintained under nitrogen at −78° C.was added in 30 min a 2.5M solution of n-butyllithium (8.8 mL, 1.10equiv) in hexane dropwise with stirring. The resulting solution wasstirred at −78° C. for 2 h. Sulfur dioxide gas was then bubbled into thesolution at −78° C. for 1 h. The reaction mixture was warmed naturallyto room temperature and the product was precipitated by the addition of50 mL of ether. The solids were collected by filtration, washed withhexane (30 mL) and dried in a vacuum oven to produce 3.2 g (66%) oflithium 4-(morpholinomethyl)benzenesulfinate as a white solid.

Step 2: Synthesis of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate

A mixture of lithium 4-(morpholinomethyl)benzenesulfinate (2.0 g, 8.10mmol, 1.43 equiv), methyl4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (1.5 g, 5.66 mmol, 1.00equiv) and potassium carbonate (780 mg, 5.65 mmol, 1.00 equiv) inN,N-dimethylformamide (60 mL) was stirred overnight at 70° C. Thereaction mixture was cooled to room temperature and the product wasprecipitated by the addition of 150 mL of ice and water. The solid wascollected by filtration, washed with 2×20 mL of water and dried in avacuum oven to afford 1.5 g (57%) of methyl4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoateas a white solid. LC-MS: (ES, m/z): 512 [M+CH₃CN+H]⁺, 471 [M+H]⁺. ¹HNMR(400 MHz, DMSO-d₆, ppm) δ 8.04 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz,2H), 7.72 (d, J=7.6 Hz, 2H), 7.52 (d, J=7.6 Hz, 2H), 4.67 (s, 2H), 3.88(s, 3H), 3.55 (s, 6H), 3.31-3.29 (d, 4H), 2.32 (s, 4H), 2.15 (s, 3H).

Step 3: Synthesis of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid

A solution of methyl4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate(1 g, 2.13 mmol, 1.00 equiv) in 6N hydrochloric acid (40 mL) wasrefluxed for 8 h. The reaction mixture was cooled to room temperaturenaturally and then diluted with 100 mL of water/ice. The precipitate wascollected by filtration, washed with 2×20 mL of water and dried in avacuum oven to give 0.7 g (72%) of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid as a white solid.

Step 4: Synthesis of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

To a solution of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid (490 mg, 1.07 mmol, 1.00 equiv), EDCI (250 mg, 1.31 mmol, 1.22equiv), HOBt (180 mg, 1.33 mmol, 1.24 equiv), triethylamine (330 mg,3.27 mmol, 3.04 equiv) and pyridin-3-ylmethanamine (330 mg, 3.06 mmol,2.84 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight atroom temperature. The product was precipitated by the addition of 60 mLice/water. The solid was collected by filtration and washed with water(1×20 mL) and dried in an oven under reduced pressure to give 0.40 g(68%) of4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 547 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6,ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=7.6 Hz, 2H),7.86 (d, J=7.6 Hz, 2H), 7.74-7.72 (m, 3H), 7.53 (d, J=7.6 Hz, 2H), 7.36(s, 1H), 4.67 (s, 2H), 4.51 (d, J=4.0 Hz, 2H), 3.55 (s, 6H), 2.32 (s,4H), 2.15 (s, 3H).

Example 61 Synthesis of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt Step 1: Synthesis of 2-(4-bromophenyl)acetylchloride

A solution of 2-(4-bromophenyl)acetic acid (20.0 g, 93.46 mmol, 1.00equiv) in thionyl chloride (40 mL) was refluxed for 2 h. The resultingmixture was concentrated under vacuum to give 20 g (92%) of2-(4-bromophenyl)acetyl chloride as a white solid.

Step 2: Synthesis of 2-(4-bromophenyl)-1-morpholinoethanone

To a solution of morpholine (16 g, 183.91 mmol, 1.98 equiv) indichloromethane (50 mL) at 0-5° C. was added a solution of2-(4-bromophenyl)acetyl chloride (21.5 g, 92.67 mmol, 1.00 equiv) indichloromethane (20 mL) dropwise with stirring. The reaction mixture wasstirred for another hour at 0˜5° C. The reaction mixture was warmed toroom temperature and diluted with 30 mL of dichloromethane. The mixturewas washed with 3×50 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum to give 19.5 g (74%) of2-(4-bromophenyl)-1-morpholinoethanone as a white solid. LC-MS: (ES,m/z): 284 [M+H]⁺.

Step 3: Synthesis of 4-(4-bromophenethyl)morpholine

To a mixture of lithium aluminum hydride (3.35 g, 88.16 mmol, 2.00equiv) in tetrahydrofuran (100 mL) maintained under nitrogen at −30° C.was added a solution of 2-(4-bromophenyl)-1-morpholinoethanone (12.5 g,44.17 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) dropwise withstirring. The reaction mixture was stirred at −30° C. for 30 min andthen at room temperature for 2 h. The reaction was then quenchedsequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueoussodium hydroxide solution and 3.5 mL of water. The solid was removed byfiltration. The filtrate was extracted with 1×150 mL of ethyl acetate.The organic layer was collected then washed with 2×30 mL of brine, driedover anhydrous sodium sulfate and concentrated under vacuum to give 11.5g (97%) of 4-(4-bromophenethyl)morpholine as a white solid. LC-MS: (ES,m/z): 311 [M+CH₃CN+H]⁺, 270 [M+H]⁺, 130, 102.

Step 4: Synthesis of lithium 4-(2-morpholinoethyl)benzenesulfinate

To a solution of 4-(4-bromophenethyl)morpholine (5.0 g, 18.59 mmol, 1.00equiv) in tetrahydrofuran (70 mL) maintained under nitrogen at −78° C.was added a. To this was added a 2.5M solution of n-butyllithium (8.2mL) dropwise with stirring at −78° C. The resulting solution was stirredfor another 2 h at −78° C. Dry sulfur dioxide gas was then bubbled intothe solution at −78° C. for 1 h. The reaction mixture was warmed to roomtemperature then diluted with 50 mL of ether to precipitate out theproduct. The solid was collected by filtration, washed with 1×20 mL ofether and dried in a vacuum oven to give 3.5 g (72%) of lithium4-(2-morpholinoethyl)benzenesulfinate as a white solid.

Step 5: Synthesis of methyl4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate

A mixture of lithium 4-(2-morpholinoethyl)benzenesulfinate (2.0 g, 7.66mmol, 1.00 equiv), methyl4-(3-(chloromethyl)-4-methylcyclopenta-1,3-dienyl)benzoate (1.5 g, 5.66mmol, 0.74 equiv) and potassium carbonate (800 mg, 5.80 mmol, 0.76equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogenovernight at 70° C. The reaction mixture was cooled to room temperatureand the product was precipitated by the addition of 150 mL of ice andwater. The solid was collected by filtration, washed with 1×20 mL ofwater and dried in a vacuum oven to give 2.1 g (57%) of methyl4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoateas a white solid. LC-MS: (ES, m/z): 485 [M+H]⁺, 437, 279, 130, 115.

Step 6: Synthesis of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride

A solution of methyl4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate(600 mg, 1.24 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) wasrefluxed for 8 h. The reaction mixture was cooled to room temperatureand concentrated under vacuum to give 0.6 g (96%) of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride as a white solid.

Step 7: Synthesis of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt

A solution of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid (600 mg, 1.28 mmol, 1.00 equiv), EDCI (290 mg, 1.52 mmol, 1.19equiv), HOBt (210 mg, 1.56 mmol, 1.22 equiv), triethylamine (390 mg,3.86 mmol, 3.02 equiv) and pyridin-3-ylmethanamine (170 mg, 1.57 mmol,1.23 equiv) in N,N-dimethylformamide (30 mL) was stirred overnight atroom temperature. The product was precipitated by the addition of 100 mLof ice/water. The solid was collected by filtration, washed with 1×30 mLof water and dried in a vacuum oven. The crude product (350 mg) waspurified by Prep-HPLC with the following conditions (2#-Waters2767-2(HPLC-08)): Column, SunFire Prep C18, 19*150 mm 5 um; mobilephase, WATER WITH 0.05% TFA and CH₃CN (10% CH3CN up to 30% in 12 min);Detector, UV 220 nm, to give 95 mg (11%) of4-(5-methyl-4-((4-(2-morpholinoethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamidetrifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 561[M+H]⁺, 323, 302, 281. ¹HNMR (400 MHz, D₂O, ppm) δ 8.75 (s, 1H), 8.67(d, J=5.2 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 8.00 (t, J=7.2 Hz, 1H),7.88-7.82 (m, 4H), 7.66 (d, J=7.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 2H), 4.75(s, 2H), 4.52 (s, 2H), 4.03 (d, J=12.8 Hz, 2H), 3.72 (t, J=12.4 Hz, 1H),3.48 (d, J=12.4 Hz, 2H), 3.33-3.29 (m, 2H), 3.14-3.10 (m, 4H), 1.97 (s,3H).

Example 62 Synthesis of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideacid trifluoroacetic acid salt Step 1: Synthesis of dimethyl2-(4-bromobenzyl)malonate

A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) andpotassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) inN,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. Asolution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00equiv) in N,N-dimethylformamide (80 mL) was then added dropwise withstirring to the reaction mixture. The resulting solution was stirred at50° C. for 2 h. Water (100 mL) was added and the mixture was extractedwith 1×400 mL of ethyl acetate. The organic layer was washed with 2×100mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as awhite solid. LC-MS: (ES, m/z): 301 [M+H]⁺, 126, 120.

Step 2: Synthesis of 2-(4-bromobenzyl)malonic acid

A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) inethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. Theresulting solution was diluted with 300 mL of ice and water thenextracted with 1×500 mL of ethyl acetate. The organic layer was washedwith 2×150 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to give 18.2 g (91%) of2-(4-bromobenzyl)malonic acid as a white solid.

Step 3: Synthesis of 3-(4-bromophenyl)propanoic acid

A solution of 2-(4-bromobenzyl)malonic acid (18 g, 66.18 mmol, 1.00equiv) in dimethylsulfoxide (50 mL) was stirred at 160° C. for 2 h. Thereaction mixture was cooled to room temperature and the product wasprecipitated by the addition of 200 mL ice and water. The solid wascollected by filtration, washed with 1×50 mL of water and dried in avacuum oven to give 14.8 g (98%) of 3-(4-bromophenyl)propanoic acid as awhite solid. LC-MS: (ES, m/z): 229 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6,ppm): δ 7.45 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 2.82-2.77 (m,2H), 2.55-2.51 (m, 2H).

Step 4: Synthesis of 3-(4-bromophenyl)propanoyl chloride

A solution of 3-(4-bromophenyl)propanoic acid (14.5 g, 63.60 mmol, 1.00equiv) in thionyl chloride (80 mL) was refluxed for 2 h. The reactionmixture was cooled to room temperature and then concentrated undervacuum to give 15.5 g (99%) of 3-(4-bromophenyl)propanoyl chloride as alight yellow oil.

Step 5: Synthesis of 3-(4-bromophenyl)-1-morpholinopropan-1-one

To a solution of morpholine (11 g, 126.44 mmol, 2.01 equiv) indichloromethane (60 mL) 0˜5° C. was added a solution of3-(4-bromophenyl)propanoyl chloride (15.5 g, 63.01 mmol, 1.00 equiv) indichloromethane (30 mL) dropwise with stirring. The resulting solutionwas stirred at 0˜5° C. for 1 h. The reaction mixture was warmed to roomtemperature. The resulting solution was diluted with 40 mL of water. Themixture was extracted with dichloromethane 2×100 mL. The combinedorganic layers was washed with 3×50 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum to give 17.4 g (93%) of3-(4-bromophenyl)-1-morpholinopropan-1-one as a white solid.

Step 6: Synthesis of 4-(3-(4-bromophenyl)propyl)morpholine

To a mixture of lithium aluminum hydride (4.4 g, 115.79 mmol, 2.00equiv) in tetrahydrofuran (120 mL) maintained under nitrogen at −30° C.was added a solution of 3-(4-bromophenyl)-1-morpholinopropan-1-one (17.2g, 57.91 mmol, 1.00 equiv) in tetrahydrofuran (80 mL) dropwise withstirring. The resulting solution was stirred at −30° C. for 30 min andat room temperature for 2 h. The reaction was quenched by the sequentialaddition of 4.4 mL of water, 13 mL of 15% aqueous sodium hydroxidesolution and 4.4 mL of water. The solid was removed by filtration andthe filtrate was extracted with 1×350 mL of ethyl acetate. The organiclayer was washed with 2×50 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum to afford 13.5 g (82%) of4-(3-(4-bromophenyl)propyl)morpholine as a light yellow oil.

Step 7: Synthesis of lithium 4-(3-morpholinopropyl)benzenesulfinate

To a solution of 4-(3-(4-bromophenyl)propyl)morpholine (5.0 g, 17.67mmol, 1.00 equiv) in tetrahydrofuran (80 mL) maintained under nitrogenat −78° C. was added in 30 min a 2.5M solution of n-butyllithium (8.0mL) in hexane dropwise with stirring. The resulting solution was stirredat −78° C. for 2 h. Sulfur dioxide gas was then bubbled into thesolution at −78° C. for 1 h and then warmed naturally to roomtemperature. The resulting solution was diluted with 60 mL of ether toprecipitate out the product. The solid was collected by filtration,washed with 2×20 mL of ether and dried in a vacuum oven to give 4.1 g(84%) of lithium 4-(3-morpholinopropyl)benzenesulfinate as a whitesolid.

Step 8: Synthesis of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate

A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(2.0 g, 7.55 mmol, 1.00 equiv), lithium4-(3-morpholinopropyl)benzenesulfinate (4.0 g, 14.55 mmol, 1.93 equiv)and potassium carbonate (1.35 g, 9.78 mmol, 1.30 equiv) inN,N-dimethylformamide (50 mL) was stirred overnight at 70° C. Theproduct was precipitated by the addition of 150 mL ice and water afterthe reaction was cooled to room temperature. The solid was collected byfiltration, washed with 2×15 mL of water and dried in a vacuum oven togive 2.8 g (74%) of methyl4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoateas a white solid. LC-MS: (ES, m/z): 499 [M+H]⁺, 115.

Step 9: Synthesis ofmethyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride

A solution of methyl4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate(2.0 g, 4.02 mmol, 1.00 equiv) in 6N hydrochloric acid (80 mL) wasrefluxed overnight. The reaction mixture was cooled to room temperatureand concentrated under vacuum to give 2.0 g (96%) of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride as a white solid. LC-MS: (ES, m/z): 485 [M+H]⁺.

Step 10: Synthesis of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideacid trifluoroacetic acid salt

A solution of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid hydrochloride (1.5 g, 2.88 mmol, 1.00 equiv), EDCI (660 mg, 3.46mmol, 1.20 equiv), HOBt (460 mg, 3.41 mmol, 1.18 equiv), triethylamine(1.16 g, 11.49 mmol, 3.98 equiv) and pyridin-3-ylmethanamine (380 mg,3.52 mmol, 1.22 equiv) in N,N-dimethylformamide (40 mL) was stirredovernight at 25-30° C. The resulting solution was diluted with 100 mL ofwater and extracted with 1×100 mL of ethyl acetate. The organic layerwas washed with 3×50 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The crude product (550 mg) was purifiedby Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH0.05% TFA and CH3CN (10% CH3CN up to 30% in 12 min, up to 100% in 1min); Detector, uv 220/254 nm, to give 400 mg (20%) of4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideacid trifluoroacetic acid salt as a white solid. LC-MS: (ES, m/z): 575[M+H]⁺, 288, 126. ¹HNMR (400 MHz, DMSO-d6, ppm): δ 8.79 (m, 1H), 8.70(d, J=4.8 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.92(d, J=8.4 Hz, 2H), 7.87-7.84 (m, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.48 (d,J=8.4 Hz, 2H), 4.62 (s, 4H), 3.98-3.94 (m, 2H), 3.64 (s, 2H), 3.42-3.39(m, 2H), 3.12-3.00 (m, 4H), 2.78-2.73 (m, 2H), 2.09 (s, 3H), 2.00-1.92(m, 2H).

Example 63 Synthesis of4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)benzamideStep 1: Synthesis of 2-(pyridin-3-yl)ethanamine

A mixture of 2-(pyridin-3-yl)acetonitrile (1 g, 8.47 mmol, 1.00 equiv),Raney nickel (1 g, 17.24 mmol, 1.00 equiv) and ammonium hydroxide (3 mL)in methanol (15 mL) was stirred under 1 atmosphere of hydrogen at roomtemperature overnight. The catalyst was removed by filtration through apad of Celite and washed with several portions of methanol. The filtrateand washings were combined and concentrated under vacuum to give 940 mg(45%) of 2-(pyridin-3-yl)ethanamine as a yellow oil. LC-MS: (ES, m/z):164 [M+CH₃CN+H]⁺, 123 [M+H]⁺, 106.

Step 2: Synthesis of4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate

To a solution of 2-(pyridin-3-yl)ethanamine (940 mg, 7.70 mmol, 5.00equiv),4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoicacid (700 mg, 1.51 mmol, 1.00 equiv), HOBt (250 mg, 1.85 mmol, 1.20equiv), EDCI (350 mg, 1.83 mmol, 1.20 equiv) in N,N-dimethylformamide(20 mL) at 30° C. was added triethylamine (460 mg, 4.55 mmol, 3.00equiv) dropwise with stirring. The reaction mixture was stirred at 30°C. overnight and then quenched by the addition of 30 mL of water/ice.The precipitate was collected by filtration, washed with water and driedin a vacuum oven to give 840 mg (98%) of tert-butyl4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylateas a yellow solid. LC-MS: (ES, m/z): 569 [M+H]⁺, 469, 361, 320, 169,126. ¹HNMR (400 MHz, DMSO-d6, ppm) δ 8.73 (s, 1H), 8.50-8.45 (d, 2H),7.99-7.94 (d, 5H), 7.74 (s, 1H), 7.38 (s, 1H), 4.54 (s, 3H), 4.07 (s,3H), 3.54 (s, 3H), 2.90 (m, 6H), 2.50-2.45 (s, 6H), 2.11 (s, 3H),1.48-1.41 (s, 16H).

Step 3: Synthesis of4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)benzamide

Excess hydrogen chloride gas was bubbled into a solution of tert-butyl4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate(840 mg, 1.48 mmol, 1.00 equiv) in dichloromethane (20 mL) maintained at0° C. in a water/ice bath. The reaction mixture was stirred at 0° C. foranother 2 h. The pH value of the solution was adjusted to 10 with 1Msodium hydroxide solution. Water (400 mL) was then added and theresulting solution was extracted with 5×200 mL of dichloromethane. Thecombined organic layers was washed with 2×600 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to give 420 mg(61%) of4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)benzamideas a white solid. LC-MS: (ES, m/z): 469 [M+H]⁺, 320, 235. ¹HNMR (400MHz, CD₃OD, ppm) δ 8.47 (s, 1H), 8.42-8.40 (d, 1H), 8.09-8.07 (d, 2H),7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (t, 1H), 4.45 (s, 2H),3.70-3.66 (t, 2H), 3.43-3.39 (m, 3H), 3.03-2.99 (t, 2H), 2.88-2.82 (m,2H), 2.50 (s, 3H), 2.34-2.31 (d, 2H), 1.91-1.88 (m, 2H).

Example 64 Synthesis of4-[5-methyl-4-[(1-methylpiperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide

A solution of4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide(322 mg, 0.69 mmol, 1.00 equiv) and paraformaldehyde (0.21 g, 10.00equiv) in formic acid (15 mL) was stirred overnight at 110° C. Theresulting mixture was concentrated under vacuum and the crude product(320 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, CH3CN/H2O (5% up to 60% in 12 min, up to 100% in 1 min,down to 5% in 1 min); Detector, UV 254 nm, to give 36.5 mg (11%) of4-[5-methyl-4-[(1-methylpiperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamideas a white solid. LC-MS: (ES, m/z): 483 [M+H]⁺, 242. ¹HNMR (400 MHz,CD₃OD, ppm): δ 8.47 (s, 1H), 8.42-8.40 (s, 1H), 8.08-8.06 (d, 2H),7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (m, 1H), 4.41 (s, 2H),3.69-3.66 (t, 2H), 3.21-3.06 (m, 1H), 3.06-2.99 (m, 4H), 2.50 (s, 3H),2.30 (s, 3H), 2.26-2.23 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.87 (m, 2H).

Example 65 Synthesis of4-[5-methyl-4-[3-(piperidin-4-yloxy)propyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetate Step 1: Synthesis of4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate

A mixture of di-tert-butyl malonate (4.3 g, 19.91 mmol, 1.99 equiv) andpotassium carbonate (2.8 g, 20.29 mmol, 2.03 equiv) inN,N-dimethylformamide (30 mL) was stirred at 65° C. for 30 min. Asolution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(2.65 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) wasthen added dropwise with stirring to the reaction mixture. The resultingsolution was stirred at 65° C. overnight and then quenched with 60 mL ofice and water. The mixture was extracted with 2×50 mL of ethyl acetate.The combined organic layers was washed with 3×30 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to give 4.0 g(90%) of methyl4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoateas a light yellow solid. LC-MS: (ES, m/z): 446 [M+H]⁺, 390, 334, 272,230, 115.

Step 2: Synthesis of2-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methyl)malonicacid

To a solution of methyl4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate(4.0 g, 8.99 mmol, 1.00 equiv) in dichloromethane (20 mL) was addedtrifluoroacetic acid (20 mL). The reaction mixture was stirred overnightat 35° C. and then concentrated under vacuum to remove dichloromethane.Saturated sodium bicarbonate solution was added to the residue until thepH value of the solution was adjusted to 2-3. The resulting solution wasextracted with 200 mL of ethyl acetate. The organic layer was washedwith 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to yield 3.0 g (100%) of2-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methyl)malonicacid as a light yellow solid. LC-MS: (ES, m/z): 334 [M+H]⁺, 272, 115.

Step 3: Synthesis of3-[2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid

A solution of2-([2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]methyl)propanedioicacid (2.0 g, 6.00 mmol, 1.00 equiv) in dimethylsulfoxide (30 mL) wasstirred at 160° C. for 30 min. The reaction mixture was cooled to roomtemperature and the product was precipitated by the addition of 150 mLice and water. The solid was collected by filtration, washed with 1×50mL of water and dried in vacuum to give 1.5 g (86%) of3-[2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acidas a white solid. LC-MS: (ES, m/z): 290 [M+H]⁺, 272, 146, 120.

Step 4: Synthesis of methyl4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate

Boron trifluoride etherate (4 g) was added dropwise with stirring to amixture of sodium borohydride (720 mg, 19.03 mmol, 2.02 equiv) intetrahydrofuran (35 mL) maintained under nitrogen at 0° C. The resultingsolution was warmed to room temperature and stirred for 2 h. The abovemixture was cooled to 0° C. then3-[2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid(2.72 g, 9.40 mmol, 1.00 equiv) was added in several batches. Thereaction mixture was stirring at room temperature overnight and thenquenched with 5 mL of methanol and 60 mL of water. The resultingsolution was extracted with 50 mL of ethyl acetate. The organic layerwas dried over anhydrous calcium chloride and concentrated under vacuumto give 2.2 g (85%) of methyl4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a whitesolid. LC-MS: (ES, m/z): 276 [M+H]⁺, 146, 115.

Step 5: Synthesis of-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate

To a solution of methyl4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate (500 mg, 1.82mmol, 1.00 equiv) and triethylamine (370 mg, 3.66 mmol, 2.01 equiv) inethyl acetate (20 mL) at −5° C. was added methanesulfonyl chloride (0.27g) dropwise with stirring. The resulting solution was warmed to roomtemperature naturally and stirred at room temperature for 1 h. Water (20mL) was added and the mixture was extracted with 1×30 mL of ethylacetate. The organic layer was washed sequentially with 1×10 mL of 1 Nhydrochloric acid, 1×10 mL of 5% sodium bicarbonate solution and 1×30 mLof brine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to give 0.55 g (86%) of methyl4-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate asa white solid. LC-MS: (ES, m/z): 354 [M+H]⁺, 258, 146, 105.

Step 6: Synthesis of4-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)propyl)-5-methyloxazol-2-yl)benzoicacid

To a solution of methyl4-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate(630 mg, 1.78 mmol, 1.00 equiv) and tert-butyl4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol, 2.79 equiv) inN,N-dimethylformamide (20 mL) maintained under nitrogen at 35° C. wasadded potassium tert-butoxide (350 mg, 3.12 mmol, 1.75 equiv) in 20 min.The resulting solution was stirred at 35° C. for another 35 min then thereaction was quenched with 50 mL of water. The pH value of the solutionwas adjusted to 2-3 with 2N hydrochloric acid. The resulting solutionwas extracted with 50 mL of ethyl acetate. The organic layer was washedwith 2×50 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to give 1.0 g of crude4-(4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)propyl)-5-methyloxazol-2-yl)benzoicacid as a white solid. LC-MS: (ES, m/z): 445[M+H]⁺, 389, 115.

Step 7: Synthesis of tert-butyl4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylate

A solution of4-[4-[3-([1-[(tert-butoxy)carbonyl]piperidin-4-yl]oxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoicacid (1.0 g, 2.25 mmol, 1.00 equiv), EDCI (560 mg, 2.92 mmol, 1.30equiv), HOBt (400 mg, 2.96 mmol, 1.32 equiv), triethylamine (800 mg,7.91 mmol, 3.51 equiv) and pyridin-3-ylmethanamine (480 mg, 4.44 mmol,1.97 equiv) in N,N-dimethylformamide (30 mL) was stirred at 35° C.overnight. The product was precipitated by the addition of 50 mL ofice/water. The solid was collected by filtration, washed with 3×30 mL ofwater and dried in a vacuum oven to give 0.8 g (67%) of tert-butyl4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylateas a white solid LC-MS-PH: (ES, m/z): 535 [M+H]⁺, 435, 367, 352, 239,102.

Step 8: Synthesis of4-[5-methyl-4-[3-(piperidin-4-yloxy)propyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetate

Excess hydrogen chloride gas was bubbled into a solution of tert-butyl4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylate(700 mg, 1.31 mmol, 1.00 equiv) in dichloromethane (20 mL) at 0° C. Theresulting solution was stirred at 0° C. for 2 h and then concentratedunder vacuum. The crude product (500 mg) was purified by Prep-HPLC withthe following conditions (Waters-1): Column, Xbridge C1819*150; mobilephase, 0.05% TFA/water; Detector, UV 220 nm, to yield 27.3 mg (4%) of4-[5-methyl-4-[3-(piperidin-4-yloxy)propyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamidetrifluoroacetate as a white solid. LC-MS: (ES, m/z): 435 [M+H]⁺, 352,306, 239, 218. ¹H-NMR (400 MHz, D₂O, ppm) δ 8.71 (s, 1H), 8.63 (d, J=5.6Hz, 1H), 8.52 (d, J=8.0 Hz, 1H), 7.99-7.95 (m, 2H), 7.84 (d, J=8.4 Hz,2H), 3.63-3.61 (m, 1H), 3.50-3.47 (m, 2H), 3.28-3.25 (m, 2H), 3.01-2.96(m, 2H), 2.57-2.53 (m, 2H), 2.28 (s, 2H), 2.03-2.00 (m, 2H), 1.84-1.71(m, 2H), 1.68-1.65 (m, 2H)

Example 66 Synthesis of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of lithium 4-(trifluoromethyl)benzenesulfinate

To a solution of 1-bromo-4-(trifluoromethyl)benzene (5.0 g, 22.32 mmol,1.00 equiv, 100%) in tetrahydrofuran (50 mL) maintained under nitrogenat −78° C. was added a 2.5M n-butyllithium solution in hexane (9.8 mL)dropwise with stirring. The resulting solution was stirred at −78° C.for 2 h then sulfur dioxide gas was bubbled continuously for 1 h intothe reaction mixture. The solution was warmed naturally to 25° C. then50 mL of ether was added. The solid was collected by filtration, washedwith 30 mL of hexane then dried in a vacuum oven to give 3.5 g (73%) oflithium 4-(trifluoromethyl)benzenesulfinate as a white solid.

Step 2: Synthesis of methyl4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate

A mixture of lithium 4-(trifluoromethyl)benzenesulfinate (700 mg, 3.24mmol, 1.72 equiv, 100%), methyl4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (500 mg, 1.89 mmol,1.00 equiv) and potassium carbonate (0.35 g) in N,N-dimethylformamide(25 mL) was stirred overnight at 70° C. The reaction mixture was cooledto room temperature then quenched by the addition of 60 mL of water andice. The solid was collected by filtration, washed with 2×20 mL of waterand dried in a vacuum oven to yield 0.7 g (85%) of methyl4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoateas a white solid. LC-MS: (ES, m/z): 481 [M+CH₃CN+H]⁺, 440 [M+H]⁺, 271,146, 105.

Step 3: Synthesis of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid

A solution of methyl4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate(700 mg, 1.59 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) wasrefluxed for 8 h. The reaction mixture was cooled to room temperatureand diluted with 100 g of water/ice. The solid was collected byfiltration, washed with 2×20 mL of water and dried in a vacuum oven toafford 0.6 g (89%) of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid as a white solid.

Step 4: Synthesis of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

A solution of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoicacid (420 mg, 0.99 mmol, 1.00 equiv), EDCI (230 mg, 1.20 mmol, 1.22equiv), HOBt (170 mg, 1.26 mmol, 1.27 equiv), triethylamine (300 mg,2.97 mmol, 3.01 equiv) and pyridin-3-ylmethanamine (140 mg, 1.30 mmol,1.31 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight atroom temperature. The product was precipitated by the addition 60 mL ofwater/ice. The solid was collected by filtration, washed with 2×20 mL ofwater and dried in a vacuum oven to give 0.20 g (39%) of4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid. LC-MS: (ES, m/z): 557 [M+CH₃CN+H]⁺, 516 [M+H]⁺, 102.¹HNMR (400 MHz, CDCl₃, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H),8.06-7.89 (m, 6H), 7.82 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H),7.38-7.36 (m, 1H), 4.84 (s, 2H), 4.51 (d, J=5.2 Hz, 2H), 2.24 (s, 3H).

Example 67 Synthesis of4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideStep 1: Synthesis of methyl4-(4-(cyclohexylthiomethyl)-5-methyloxazol-2-yl)benzoate

A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate(6.0 g, 22.64 mmol, 1.00 equiv), cyclohexanethiol (3.9 g, 33.62 mmol,1.50 equiv) and cesium carbonate (11.1 g, 34.05 mmol, 1.50 equiv) inN,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at50° C. The reaction was then quenched by the addition of 30 mL of water.The precipitate was collected by filtration and washed with 3×10 mL ofhexane to give 4.5 g (58%) of methyl4-(4-(cyclohexylthiomethyl)-5-methyloxazol-2-yl)benzoate as a whitesolid after drying under vacuum.

Step 2: Synthesis of methyl4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoate

To a solution of methyl4-(4-(cyclohexylthiomethyl)-5-methyloxazol-2-yl)benzoate (2.0 g, 5.80mmol, 1.00 equiv) in chloroform (20 mL) at 0˜5° C. was added3-chloroperoxybenzoic acid (2.5 g, 14.53 mmol, 2.50 equiv), in portionsin 1.5 h. The resulting solution was stirred at 0˜5° C. for 1 h. Thereaction mixture was diluted with 100 mL of dichloromethane then washedsequentially with 3×100 mL of aqueous sodium bisulphate solution, 2×50mL of 1M sodium hydroxide solution and 3×50 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to give 1.4 g (64%) of methyl4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoate as a whitesolid. LC-MS: (ES, m/z): 378 [M+H]⁺, 271, 146, 105.

Step 3: Synthesis of4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid

A solution of methyl4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoate (1.0 g,2.65 mmol, 1.00 equiv) in 6N hydrochloric acid (20 mL) was refluxedovernight. The reaction mixture was cooled to room temperature and 30 mLof water and ice were added. The precipitate ws collected by filtration,washed with 3×20 mL of hexane and dried in a vacuum oven to give 0.85 g(88%) of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoicacid as a white solid. LC-MS: (ES, m/z): 365 [M+H]⁺, 341, 257, 216, 189,146, 115.

Step 4: Synthesis of4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

A solution of4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid (500mg, 1.38 mmol, 1.00 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol,1.20 equiv), EDCI (320 mg, 1.68 mmol, 1.20 equiv), HOBt (220 mg, 1.63mmol, 1.20 equiv) and triethylamine (420 mg, 4.16 mmol, 3.00 equiv) inN,N-dimethylformamide (10 mL) was stirred overnight at room temperature.The reaction mixture was diluted with 15 mL of water and ice. Theprecipitate was collected by filtration, washed with water and dried ina vacuum oven to give 0.25 g (40%) of4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamideas a white solid LC-MS: (ES, m/z): 454 [M+H]⁺, 347, 306, 238, 120 ¹HNMR(400 MHz, CDCl₃, ppm) δ 8.97 (s, 1H), 8.57 (s, 2H), 8.21-8.05 (t, 4H),7.54 (s, 2H), 4.73 (s, 2H), 4.17 (s, 2H), 3.02-2.98 (d, 2H), 2.90-2.50(m, 6H), 2.31-2.20 (d, 2H), 1.95 (s, 2H), 1.74-1.61 (m, 3H), 1.29 (s, 3H

Example 68 Synthesis of 3-(dimethylamino)phenyl4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl] piperidine-1-carboxylate Step1: Synthesis of 3-(dimethylamino)phenyl carbonochloridate

Sodium hydride (130 mg, 3.25 mmol, 1.11 equiv, 60%) was added in severalbatches to a solution of 3-(dimethylamino)phenol (400 mg, 2.92 mmol,1.00 equiv) in tetrahydrofuran (15 mL). The mixture was stirred at 0° C.for 30 min then ditrichloromethyl carbonate (296.74 mg, 1.00 mmol, 0.34equiv) was added in several batches to the mixture at 0° C. Theresulting solution was stirred for 4 h at 50° C. and used in the nextstep without any purification

Step 2: Synthesis of 3-(dimethylamino)phenyl4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]piperidine-1-carboxylate

To a solution of4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-Nyridin-3-ylmethyl)benzamide(1.2 g, 2.64 mmol, 1.76 equiv) in dichloromethane (15 mL) was added the3-(dimethylamino)phenyl chloroformate (300 mg, 1.50 mmol, 1.00 equiv)dropwise. The resulting solution was stirred overnight at 30° C. Theresulting mixture was concentrated under vacuum and the residue waspurified on an aluminum oxide column eluted withdichloromethane/methanol (0/100-80/20) to give 230 mg (25%) of3-(dimethylamino)phenyl4-[[(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)methane]sulfonyl]piperidine-1-carboxylateas a white solid. LC-MS: (ES, m/z): 618 [M+H]⁺, 330, 310, 169, 126, 100.¹HNMR (400 MHz, DMSO-d6, ppm): δ 9.25 (s, 1H), 8.57 (s, 1H), 8.47 (s,1H), 8.04 (s, 4H), 7.76 (d, 1H), 7.38 (t, 1H), 7.15 (t, 1H), 6.56 (d,1H), 6.43 (s, 1H), 6.38 (s, 1H), 4.58-4.52 (m, 4H), 4.22 (d, 2H), 3.47(t, 1H), 3.10 (s, 1H), 3.05 (s, 1H), 2.95 (s, 6H), 2.48 (s, 3H), 2.22(d, 2H), 1.69 (s, 2H).

Example 68A Synthesis ofS-((5-methyl-2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)oxazol-4-yl)methyl)ethanethioateStep 1:4-(4-(chloromethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoic acid was treated withN-hydroxysuccinimide in presence of DCC in THF to form active ester2,5-dioxopyrrolidin-1-yl4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate, which was coupled withpyridin-3-ylmethanamine to afford the tittle in 80% yield. [M+H]⁺ m/z342.

Step 2:S-((5-methyl-2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)oxazol-4-yl)methyl)ethanethioate

To a solution of4-(4-(chloromethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide(1.00 equiv) in acetone, potassium ethanethioate (1.50 equiv), andpotassium iodide (0.10 equiv) were added. The resulting solution wasstirred overnight at room temperature and was diluted with 100 mL ofwater. The resulting solution was extracted with 3×150 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×100 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum to obtain methyl4-(4-(acetylthiomethyl)-5-methyloxazol-2-yl)benzoate as a yellow solid(96%). [M+H]⁺ m/z 382.

Example 68B4-(5-methyl-4-((morpholinosulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

N-Chlorosuccinimide (1.05 g, 7.8 mmole, 3 eq) was dissolved in a mixtureof HCl (2N)/acetonitrile (20 ml) andS-((5-methyl-2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)oxazol-4-yl)methyl)ethanethioate(1 g, 2.6 mmole, 1 eq) previously dissolved in a mixture HCl(2N)/acetonitrile (10 ml) was added. The reaction mixture was stirred at5-10° C. until a white precipitate forms followed by an additional 15min at the same temperature. The mixture was quickly added to a solutionof morpholine (0.9 ml. 10.4 mmole, 4 eq) in acetonitrile (12 ml) andstirred for an additional 10 min. The mixture was quenched with asaturated solution of NaHCO₃, with EtOAc (×3). The organic layers werecombined, washed with brine dried (Na₂SO₄) and concentrated underreduced pressure. The crude material was purified by flashchromatography to obtain the desired product (370 mg). ¹H NMR (DMSO-d6,ppm) δ 9.24 (1H, t), 8.56 (1H,$), 8.46 (1H, d), 8.02 (4H, s), 7.74 (1H,d), 7.35 (1H, dd), 4.5 (4H, m), 4.40 (4H, t), 4.46 (4H, t), 2.45 (3H,s); [M+H]⁺ m/z 457.

Example 68C4-(4-(((4-isopropylpiperazin-1-yl)sulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide

Synthesized according to the method described for example 68B using1-isopropylpiperazine. ¹H NMR (DMSO-d6, ppm) δ 9.24 (1H, t), 8.56 (1H,s), 8.46 (1H, d), 8.02 (4H, s), 7.73 (1H, d), 7.36 (1H, dd), 4.41 (2H,d), 4.42 (2H, s), 3.18 (4H, t), 2.68 (m, 1H), 2.5 (4H, m), 2.45 (3H, s),0.93 (6H, d); [M+H]⁺ m/z 498.

Example 69 Synthetic Lethal Targeting of Glucose Metabolism in RenalCarcinoma

Cell Culture.

RCC4 parental and RCC4 with VHL-reintroduced (RCC4/VHL), SN12C andSN12C-CSCG-VHL shRNA were maintained in DMEM supplemented with 10% FCS.

Cell Viability Assays.

For2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide(XTT) assays, five thousand cells were plated in 96-well plates. Thenext day, vehicle (DMSO) or drug was added by serial dilution. Four dayslater, media were aspirated, XTT solution (0.3 mg/ml of XTT (Sigma),2.65 mg/ml N-methyl dibenxopyrazine methyl sulfate (Simga) in phenolred-free media) was added, and the plates were incubated at 37° C. for1-2 hours. Metabolism of XTT was quantified by measuring the absorbanceat 450 nm. IC₅₀s were calculated using linear interpolation. Forclonogenic survival assays, three hundred cells were plated per 60 mmtissue culture dish. The cells were allowed to attach overnight and thentreated with vehicle or drug for 14 days. Colonies were fixed andstained with crystal violet (0.1% crystal violet in 95% ethanol). Allconditions were measured in triplicate and each experiment was done induplicate or triplicate. To determine necrosis, cells were treated withdrug for a given time point. Media and cells were collected,centrifugated, and resuspended in 0.4% trypan blue (Invitrogen). Liveand dead cells were counted on a hematocytometer.

IC₅₀ values and selectivity ratios for certain exemplary compounds aredescribed below. The designation A reflects an IC₅₀ of <1 nM; B reflectsan IC₅₀ ranging from 1 to 20 nM; and C is an IC₅₀ of >20 nM. Thedesignation “a” reflects a ratio of RCC4/RCC-VHL+ ranging from 1 to ≦10;“b” reflects from 10 to ≦100; “c” reflects a ratio of >100. Compounds1-29 have an IC50 value of ≦10 μM when tested in the above assay.

TABLE 1 SN IC₅₀ RCC4 μM Ratio II-1 B a II-2 C nd II-3 B a II-4 B a II-5B a II-6 C nd II-7 C nd II-8 C a Ratio = IC₅₀RCC4/VHL/IC₅₀RCC4

TABLE 1 Ratio (IC50 RCC4 Proficient IC₅₀ RCC4 VHL)/IC50 RCC4 DeficientExample nM VHL) Example C b 39 Example A b 40 Example C b 41 Example A b42 Example A b 43 Example C b 44 Example B b 45 Example A b 46 Example Cb 47 Example A b 48 Example A b 49 Example C b 50 Example A b 51 ExampleA a 52 Example A a 53 Example A b 54 Example A a 55 Ratio =IC₅₀RCC4/VHL/IC₅₀RCC4

Example 70 Clonogenic Assay

Three hundred cells are plated into 60-mm tissue culture dishes in DMEM.The next day, cells are treated with vehicle or drug and are furtherincubated for an additional 10 days. After 10 days, the media is removedand colonies are fixed and stained in 95% ethanol and 0.1% crystalviolet for 15 minutes. The stain is removed and plates are washed indeionized water. Colonies are quantified. All conditions are measured intriplicate and all experiments are performed in triplicate.

Example 71 Glucose Uptake

One hundred thousand cells are plated into 6-well plates. The followingday, the cells are treated with vehicle or drug and incubated for theindicated time. Cells are washed twice in phosphate buffered saline andlow glucose media is added for 30 minutes. Cells are then incubated with0.5 microCi of tritiated-2-deoxyglucose and incubated for an hour at 37°C. Cells are washed twice in PBS and then lysed in 0.2 N NaOH and 0.2%SDS. Lysates are transferred to scintillation tubes with scintillationfluid and quantified by scintillation counter.

Example 72 In Vivo Experiments

Five million cells are injected into the flanks of nu/nu mice (4-6 weeksold males) and allowed to grow to approximately 50 mm³. The mice areinjected daily by intra-peritoneal to deliver either vehicle or drug.Tumors are measured every other day and tumor volume is calculated as0.5 length by width squared.

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthherein be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims

What is claimed is:
 1. A compound selected from the group consisting of4-(5-methyl-4-((piperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(5-methyl-4-((4-methylpiperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-((4-isobutylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-((4-tert-butylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-((4-cyclopropylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(5-methyl-4-((4-(2,2,2-trifluoroethyl)piperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(5-methyl-4-(morpholinosulfonylmethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-((4-isopropylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(5-methyl-4-(((4-neopentylpiperazin-1-yl)sulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-(((4-ethylpiperazin-1-yl)sulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,4-(4-(((4-cyclobutylpiperazin-1-yl)sulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,and4-(5-methyl-4-((thiomorpholinosulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1 wherein the compound is4-(5-methyl-4-((piperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide.3. The compound of claim 1 wherein the compound is4-(5-methyl-4-((4-methylpiperazin-1-ylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide.4. The compound of claim 1 wherein the compound is4-(4-((4-isobutylpiperazin-1-ylsulfonyl)methyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide.5. The compound of claim 1 wherein the compound is4-(5-methyl-4-(morpholinosulfonylmethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide.6. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 7. A method for treating renalcarcinoma mediated by HIF-1α and/or HIF-2α, the method comprisingadministering to a subject a compound as defined in claim 1.